Mitochondrial Adaptations to Variable Environments and Their Role in Animals’ Stress Tolerance

Inna, Sokolova,

doi:10.1093/icb/icy017

Mitochondrial Adaptations to Variable Environments and Their Role in Animals’ Stress Tolerance

Inna, Sokolova, 2018-09-01 00:00:00 Abstract Mitochondria are the key organelles involved in energy and redox homeostasis, cellular signaling, and survival. Animal mitochondria are exquisitely sensitive to environmental stress, and stress-induced changes in the mitochondrial integrity and function have major consequences for the organismal performance and fitness. Studies in the model organisms such as terrestrial mammals and insects showed that mitochondrial dysfunction is a major cause of injury during pathological conditions and environmental insults such as hypoxia, ischemia-reperfusion, and exposure to toxins. However, animals from highly stressful environments (such as the intertidal zone of the ocean) can maintain mitochondrial integrity and function despite intense and rapid fluctuations in abiotic conditions and associated changes in the intracellular milieu. Recent studies demonstrate that mitochondria of intertidal organisms (including mollusks, crustaceans, and fish) are capable of maintaining activity of mitochondrial electron transport system (ETS), ATP synthesis, and mitochondrial coupling in a broad range of temperature, osmolarity, and ion content. Mitochondria of intertidal organisms such as mollusks are also resistant to hypoxia-reoxygenation injury and show stability or even upregulation of the mitochondrial ETS activity and ATP synthesis capacity during intermittent hypoxia. In contrast, pH optima for mitochondrial ATP synthesis and respiration are relatively narrow in intertidal mollusks and may reflect adaptation to suppress metabolic rate during pH shifts caused by extreme stress. Sensitivity to anthropogenic pollutants (such as trace metals) in intertidal mollusks appears similar to that of other organisms (including mammals) and may reflect the lack of adaptation to these evolutionarily novel stressors. The mechanisms of the exceptional mitochondrial resilience to temperature, salinity, and hypoxic stress are not yet fully understood in intertidal organisms, yet recent studies demonstrate that they may involve rapid modulation of the ETS capacity (possibly due to post-translation modification of mitochondrial proteins), upregulation of antioxidant defenses in anticipation of oxidative stress, and high activity of mitochondrial proteases involved in degradation of damaged mitochondrial proteins. With rapidly developing molecular tools for non-model organisms, future studies of mitochondrial adaptations should pinpoint the molecular sites associated with the passive tolerance and/or active regulation of mitochondrial activity during stress exposures in intertidal organisms, investigate the roles of mitochondria in transduction of stress signals, and explore the interplay between bioenergetics and mitochondrial signaling in facilitating survival in these highly stressful environments. Mitochondria as the central hub of stress tolerance Mitochondria are the hallmark of eukaryotic life involved in all essential cellular processes (Lane 2005). They provide over 90% of cellular ATP in animals (with a few exceptions of obligate anaerobes) and serve as a cellular hub that connects energy metabolism, stress sensing, signaling, and cell survival (Lane 2005; Naquet et al. 2016; Monlun et al. 2017). Studies in model organisms such as terrestrial mammals and insects show that mitochondria are exquisitely sensitive to environmental stress and act both as a target of stress and the coordinating center for the adaptive cellular response (Fig. 1). Mitochondrial stress can impair the ATP supply of the cell and lead to oxidative injury if the mitochondrial production of reactive oxygen species (ROS) exceeds the capacity of cellular antioxidants to curb the damage (Vakifahmetoglu-Norberg et al. 2017). Studies in mammals also show that stressed mitochondria release important signaling molecules engaging pleiotropic cellular mechanisms to mitigate or repair the stress-induced damage (Bohovych and Khalimonchuk 2016; Naquet et al. 2016). Mitochondrially-produced metabolic intermediates can act as substrates for post-translation regulation of the enzymes through acetylation, succinylation, and phosphorylation (Naquet et al. 2016). In mammalian models, mitochondria also play a key role in the innate immunity through activation of signaling proteins, release of ROS, and other danger signals such as mitochondrial DNA (mtDNA) and cardiolipin (Monlun et al. 2017). Notably, some multifunctional mitochondrial proteins and mitochondria-derived stress signals regulate both oxidative phosphorylation (OXPHOS) and the immune response thus providing the molecular basis for the cross-talk between mitochondrial bioenergetics and stress defense (Lartigue and Faustin 2013; Monlun et al. 2017). While the complexity of the mitochondrial bioenergetic and signaling network is not yet fully understood, it is increasingly evident that maintenance of the mitochondrial integrity and mitochondrially-derived cellular signaling are critical for cellular homeostasis and survival (Lane 2005; Bohovych and Khalimonchuk 2016; Vakifahmetoglu-Norberg et al. 2017). If these mechanisms fail and cellular injury accumulates, mitochondria initiate programmed death pathways leading to elimination of the damaged cells and potentially culminating in organ failure and mortality (Vakifahmetoglu-Norberg et al. 2017). Fig. 1 View largeDownload slide The mitochondrial stress sensing and response cascade based on the studies of model systems such as rodents, Drosophila and mammalian cell lines. Mitochondrial stress commonly suppresses mitochondrial oxidative phosphorylation (OXPHOS) and activity of the electron transport chain (ETS), and elevates electron slip resulting in ROS production. These changes can result in the energy deficiency due to the mismatch between the cellular ATP demand and mitochondrial ATP generation and oxidative injury if the antioxidant system cannot cope with the increased ROS production. Mitochondrial stress results in the release of important second messengers and stress signals such as ROS and Ca2+, which regulate the cellular signaling cascades including the hypoxia-inducible factor 1 (HIF-1), AMP kinase, and other stress-responsive kinases that ultimately lead to upregulation of the antioxidant defense, ATP synthesis, and nutrient recycling through autophagy. Furthermore, mtDNA and cardiolipin act as danger-associated molecular patterns (DAMPs) that along with other mitochondrial signals such as MAVS regulate immune response and inflammation. Mitochondrially-produced metabolites can also serve as substrates for post-translational modifications (phosphorylation, succinylation, and acetylation) of proteins that regulate the cellular homeostasis and metabolic flux. When successful, the protective mitochondrially-driven responses assist in reinstating the cellular homeostasis. However, excessive mitochondrial stress or failure of the adaptive response results in unmitigated mitochondrial damage and release of the apoptotic signals triggering cell death. Fig. 1 View largeDownload slide The mitochondrial stress sensing and response cascade based on the studies of model systems such as rodents, Drosophila and mammalian cell lines. Mitochondrial stress commonly suppresses mitochondrial oxidative phosphorylation (OXPHOS) and activity of the electron transport chain (ETS), and elevates electron slip resulting in ROS production. These changes can result in the energy deficiency due to the mismatch between the cellular ATP demand and mitochondrial ATP generation and oxidative injury if the antioxidant system cannot cope with the increased ROS production. Mitochondrial stress results in the release of important second messengers and stress signals such as ROS and Ca2+, which regulate the cellular signaling cascades including the hypoxia-inducible factor 1 (HIF-1), AMP kinase, and other stress-responsive kinases that ultimately lead to upregulation of the antioxidant defense, ATP synthesis, and nutrient recycling through autophagy. Furthermore, mtDNA and cardiolipin act as danger-associated molecular patterns (DAMPs) that along with other mitochondrial signals such as MAVS regulate immune response and inflammation. Mitochondrially-produced metabolites can also serve as substrates for post-translational modifications (phosphorylation, succinylation, and acetylation) of proteins that regulate the cellular homeostasis and metabolic flux. When successful, the protective mitochondrially-driven responses assist in reinstating the cellular homeostasis. However, excessive mitochondrial stress or failure of the adaptive response results in unmitigated mitochondrial damage and release of the apoptotic signals triggering cell death. Exposure to environmental stressors such as heat or cold shock, osmotic stress, toxins, or lack of oxygen can shift the mitochondrial balancing act from the adaptive response to cell death due to the energy deficiency and/or the overwhelming mitochondrial or cellular damage (Fig. 1) (Bohovych and Khalimonchuk 2016; Vakifahmetoglu-Norberg et al. 2017). However, many eukaryotes (such as the inhabitants of the intertidal zones of the seas) are capable of surviving and maintaining mitochondrial homeostasis despite the frequent and drastic fluctuations in environmental conditions. Intertidal zone with its alternating periods of immersion and emersion, extreme fluctuations of temperature, salinity, pH, hydrodynamic forces, and desiccation stress is one of the most stressful environments for metazoan life (Helmuth et al. 2002; Richards 2011; Jensen and Denny 2016). Oxygen concentrations in the intertidal rock pools can fluctuate from near anoxia to hyperoxia (∼300–400% air saturation) over a daily cycle, and desiccation avoidance behaviors (such as shell closure during the low tide) may cause hypoxia and anoxia by limiting the gas exchange (Stephenson et al. 1934; Truchot and Duhamel-Jouve 1980; Kurochkin et al. 2009). Oxygen fluctuations are typically accompanied by the major fluctuations of pH and CO2 levels (Stephenson et al. 1934; Truchot and Duhamel-Jouve 1980). Temperature in intertidal habitats can change by 10–30° within a few hours reaching values in excess of 35–40°C during summer low tides (Sokolova and Boulding 2004; Cherkasov et al. 2007b; Helmuth et al. 2016). Furthermore, salinity may rapidly and dramatically fluctuate due to the evaporation and precipitation events. These changes pose major challenges to homeostatic mechanisms of intertidal organisms, especially those that have limited capacity for regulating the internal milieu such as body temperature, osmolarity, pH, or ionic concentration of the body fluids. In these organisms (including many intertidal invertebrates), the mitochondrial function must be maintained despite fluctuating intracellular conditions and restored after major physiological disruptions such as extreme temperatures or prolonged lack of oxygen. Marine mollusks belong to the ecologically dominant organisms in the intertidal zone and have successfully adapted to harsh life between the tides, representing an excellent model system to investigate mitochondrial adaptations to stress. Metabolic adaptations of intertidal mollusks have been extensively studied, and metabolic rate depression has emerged as a major adaptive mechanism to extreme stress (Guppy et al. 1994; Storey 2002; Sokolova et al. 2011). It involves a coordinated suppression of ATP consumption and production to conserve energy reserves, reduce accumulation of metabolic wastes, and support the membrane integrity and ion homeostasis at the expense of the less essential processes (Hochachka et al. 1996). If aerobic ATP production decreases due to the mitochondrial failure or lack of oxygen, it can be supplemented and/or replaced by anaerobic pathways (Sommer et al. 1997; Sommer and Pörtner 1999; Sokolova and Pörtner 2003; Bagwe et al. 2015). Notably, many stress-tolerant intertidal invertebrates evolved efficient anaerobic glycolytic pathways with higher yield of ATP, less metabolic protons, and volatile end products that can be released from the body to mitigate toxicity (Hochachka and Mommsen 1983; Sokolova et al. 2011). Furthermore, stress-tolerant intertidal organisms typically have high levels of glycolytic substrates and tissue buffering capacity to prevent excessive cellular acidosis due to anaerobiosis (Eberlee and Storey 1984; Sokolova et al. 2000b). Together, these metabolic adjustments allow intertidal organisms to survive without oxygen, food, or water for days to months, depending on the environmental temperature (Hochachka and Lutz 2001; Rebecchi et al. 2007). While regulation of energy metabolism is recognized for its central role in adaptations to environmental stress in the intertidal zone, an important piece of the overall puzzle is still lacking—namely, understanding how the mitochondrial function is regulated to sustain energy metabolism and prevent cellular damage during extreme stress. Here I provide an overview of mitochondrial responses of intertidal organisms to environmental stressors (including temperature, salinity, hypoxia, pH, and trace metals) focusing on the functional traits relevant to ATP generation, mitochondrial efficiency, and cellular redox balance (Table 1 and Fig. 2), discuss the potential roles of mitochondrial resistance for environmental stress tolerance, and identify important gaps in our knowledge of mitochondrial physiology of intertidal animals that warrant further investigation. Table 1 Terminology and common approaches used to assess bioenergetics-related traits in mitochondria of intertidal organisms discussed in this review Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production a In different studies, OXPHOS, LEAK, and ETS fluxes are assessed with NADH-linked substrates such as pyruvate or glutamate (activating Complexes I, III, and IV), FADH2-linked substrates such as succinate (activating Complexes II, III, and IV), or a mixture of NADH- and FADH2-linked substrates that fully activate ETS flux. Table 1 Terminology and common approaches used to assess bioenergetics-related traits in mitochondria of intertidal organisms discussed in this review Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production a In different studies, OXPHOS, LEAK, and ETS fluxes are assessed with NADH-linked substrates such as pyruvate or glutamate (activating Complexes I, III, and IV), FADH2-linked substrates such as succinate (activating Complexes II, III, and IV), or a mixture of NADH- and FADH2-linked substrates that fully activate ETS flux. Fig. 2 View largeDownload slide Schematic representation of the common bioenergetic-related functions assessed in mitochondria. (A) Complexes I and II of the mitochondrial electron transport system (ETS) transfer electrons from NADH-linked (e.g., pyruvate) or FADH2-linked (e.g., succinate) substrates, respectively, to coenzyme Q junction (Q). The electrons from coenzyme Q are further transferred via Complex III to cytochrome c oxidase (Complex IV) of the ETS, which reduces oxygen to water. Free energy released during the electron transport is used by Complexes I, III, and IV to pump protons from the mitochondrial matrix into the intermembrane space of the mitochondria thereby creating the electrochemical proton gradient across the inner mitochondrial membrane. The energy conserved in this gradient is used to drive the ATP synthesis as the protons flow through the mitochondrial FO, F1-ATPase back into the matrix. Thereby, creation of the proton gradient by ETS and its dissipation by FO, F1-ATPase serve as a mechanism that couples oxidation of energy-rich organic substrates to ATP generation. Joint activities of ETS and FO, F1-ATPase represent mitochondrial oxidative phosphorylation (OXPHOS). Some of the protons, however, may leak back into the mitochondrial matrix bypassing FO, F1-ATPase thereby dissipating the mitochondrial proton gradient without the concomitant ATP production (LEAK). Electrons may slip from the ETS complexes (in particular, Complexes I and III) onto oxygen (not shown) resulting in the incomplete reduction of oxygen to superoxide and initiating the cascade of ROS production. (B) Mitochondrial coupling efficiency depends on the interplay between the processes that create and dissipate the proton motive force (Δp, the electrochemical, and pH gradient across the inner mitochondrial membrane). Substrate oxidation subsystem (including tricarboxylic acid cycle, substrate transporters, and ETS) generates Δp (empty arrow), whereas phosphorylation subsystem and proton leak dissipate Δp (filled arrows). Fig. 2 View largeDownload slide Schematic representation of the common bioenergetic-related functions assessed in mitochondria. (A) Complexes I and II of the mitochondrial electron transport system (ETS) transfer electrons from NADH-linked (e.g., pyruvate) or FADH2-linked (e.g., succinate) substrates, respectively, to coenzyme Q junction (Q). The electrons from coenzyme Q are further transferred via Complex III to cytochrome c oxidase (Complex IV) of the ETS, which reduces oxygen to water. Free energy released during the electron transport is used by Complexes I, III, and IV to pump protons from the mitochondrial matrix into the intermembrane space of the mitochondria thereby creating the electrochemical proton gradient across the inner mitochondrial membrane. The energy conserved in this gradient is used to drive the ATP synthesis as the protons flow through the mitochondrial FO, F1-ATPase back into the matrix. Thereby, creation of the proton gradient by ETS and its dissipation by FO, F1-ATPase serve as a mechanism that couples oxidation of energy-rich organic substrates to ATP generation. Joint activities of ETS and FO, F1-ATPase represent mitochondrial oxidative phosphorylation (OXPHOS). Some of the protons, however, may leak back into the mitochondrial matrix bypassing FO, F1-ATPase thereby dissipating the mitochondrial proton gradient without the concomitant ATP production (LEAK). Electrons may slip from the ETS complexes (in particular, Complexes I and III) onto oxygen (not shown) resulting in the incomplete reduction of oxygen to superoxide and initiating the cascade of ROS production. (B) Mitochondrial coupling efficiency depends on the interplay between the processes that create and dissipate the proton motive force (Δp, the electrochemical, and pH gradient across the inner mitochondrial membrane). Substrate oxidation subsystem (including tricarboxylic acid cycle, substrate transporters, and ETS) generates Δp (empty arrow), whereas phosphorylation subsystem and proton leak dissipate Δp (filled arrows). Mitochondrial responses to temperature Intertidal organisms including invertebrates and fish display high thermal tolerance of mitochondrial functions and broad phenotypic plasticity of mitochondrial metabolism during thermal acclimation (Dahlhoff and Somero 1993; Cherkasov et al. 2010; Hilton et al. 2010). Thus, mitochondria of an intertidal triplefin fish (Bellapiscis medius) were able to maintain higher OXPHOS flux and ETS activity as well as better coupling (indicated by higher RCR) at elevated temperature (30°C) compared with two sympatric subtidal species (Forsterygion varium and F. malcolmi) (Hilton et al. 2010). Temperature tolerance threshold for the mitochondrial OXPHOS or ETS activity (assessed as the Arrhenius breakpoint temperature [ABT] beyond which the respective mitochondrial function is inhibited or disrupted) is also higher in intertidal organisms compared with their subtidal counterparts. Thus, the ABT for the mitochondrial ETS activity was 38–44°C in intertidal (green, red, and pink) abalone, depending on the acclimation temperature (5–23°C) and increased by 0.5–0.6°C per 1°C rise in the acclimation temperature (Dahlhoff and Somero 1993). In contrast, the ABT for the mitochondrial ETS activity of a subtidal (pinto) abalone was considerably lower (32–35°C) and did not show an adaptive upward shift with warm acclimation (Dahlhoff and Somero 1993). The ABT for OXPHOS rate in mitochondria of an intertidal mud crab Scylla serrata was ∼37°C, and the mitochondria could maintain a stable rate of ATP generation between 25°C and 37°C (Paital and Chainy 2014). A significant drop in OXPHOS rate and the loss of coupling were found only at 40°C in the mud crab (Paital and Chainy 2014). High thermal tolerance of mitochondrial functions in intertidal species likely represents a safety margin that permits these organisms to survive periodic thermal extremes (up to 35–40°C) during the summer low tides (Sokolova and Boulding 2004; Cherkasov et al. 2007b; Helmuth et al. 2016). While the thermal tolerance thresholds for mitochondrial activity are shifted to higher levels in intertidal organisms, the mechanisms of temperature-induced mitochondrial disruption appear to be similar in eurythermal and stenothermal species of invertebrates. Generally, elevated temperature stress results in the reduced mitochondrial coupling (shown by lower RCR) and excess ROS generation as shown in intertidal bivalves Crassostrea virginica and Mya arenaria (Abele et al. 2002; Sokolova 2004; Cherkasov et al. 2006a, 2007a, 2010), a lugworm Arenicola marina (Keller et al. 2004), and a mud crab S. serrata (Paital and Chainy 2014). A similar pattern of reduced mitochondrial coupling and elevated ROS production (albeit occurring as a lower temperature) was found during warming in mitochondria of stenothermal bivalves such as an Antarctic clam Laternula elliptica (Abele et al. 2002; Peck et al. 2002; Heise et al. 2003). In these organisms, reduced mitochondrial coupling at elevated temperature reflects higher thermal sensitivity of the proton leak compared with the OXPHOS rate (Peck et al. 2002; Keller et al. 2004; Sokolova 2004; Cherkasov et al. 2006a, 2006b; Paital and Chainy 2014). Mild mitochondrial uncoupling during warming due to the elevated proton leak (that dissipates the protonmotive force Δp) may partially alleviate the ROS production which increases exponentially with increasing Δp (Miwa and Brand 2003). Interestingly, extreme temperatures (4°C and 42°C) also lead to the reduced mitochondrial coupling and relatively high mitochondrial proton leak in mammalian cells (Lemieux et al. 2017; Mitov et al. 2017). This indicates that the differential thermal sensitivity of the mitochondrial OXPHOS and proton leak may be common in animal mitochondria and not restricted to ectotherms. Changes in the mitochondrial density have also been implicated in adaptive metabolic responses to temperature in aquatic ectotherms. Typically, acclimation or adaptation to colder temperatures results in a compensatory increase of the mitochondrial density as shown in marine invertebrates and fish from different latitudes (Johnston et al. 1998; Sommer and Pörtner 2002; Cherkasov et al. 2010). Seasonal acclimatization also results in elevated mitochondrial content in winter and lower mitochondrial density in summer as was shown in intertidal mollusks C. virginica (Cherkasov et al. 2010) and lugworms A. marina (Sommer and Pörtner 2004). Mitochondrial proliferation in the cold may assist in the metabolic compensation by maintaining ATP production at lower temperatures and reducing diffusion distance for oxygen in the cell (Tyler and Sidell 1984; Londraville and Sidell 1990). Alternatively, a decrease in the mitochondrial density in summer may minimize the maintenance costs due to the increased mitochondrial proton leak at high temperatures (Peck et al. 2002; Keller et al. 2004). Effects of osmolarity and ion content Mitochondria of intertidal mollusks such as clams, oysters, and mussels are highly tolerant to the shifts in osmolarity and ionic strength of the media, with the optima for OXPHOS and mitochondrial coupling spanning the breadth of 400–500 mOsm around the species-specific optimum (Ballantyne and Storey 1983, 1984; Ballantyne and Moon 1985; Ballantyne and Moyes 1987a, 1987b, 1987c). Furthermore, mitochondria of intertidal and estuarine mollusks possess considerable plasticity and can adjust their osmotic optima during acclimation and acclimatization. Thus, acute hypoosmotic stress (150 mOsm, ∼300 mOsm below the acclimation osmolarity) led to a suppressed coupling, OXPHOS and COX capacity in gill mitochondria of a soft-shell clam M.arenaria, but this effect was fully reversed and the mitochondrial function restored after acclimation to low (150 mOsm) or fluctuating (150–450 mOsm) salinity (Haider et al. 2017). Acclimation to lower salinity also shifted the osmotic optima for mitochondrial OXPHOS and coupling in the gills of the eastern oysters C. virginica (Ballantyne and Moyes 1987a). Notably, compatible osmolytes such as taurine that accumulate in the molluscan cells during salinity shifts may also play an important role in mitochondria adjustments by exerting mitoprotective effects at high osmolarity, as shown in the Pacific oyster Crassostrea gigas (Sokolov and Sokolova 2018). Taken together, these data indicate that the mitochondria of intertidal mollusks are osmotically robust, plastic, and can maintain the bioenergetic capacity despite the salinity shifts. This likely reflects adaptations of the mitochondrial machinery to osmoconformity which results in shifts of intracellular osmolarity to match the ambient salinity. The mitochondria-dependent redox signaling and oxidative stress during the osmotic shifts remains a relatively unexplored area of mitochondrial physiology. Hyperosmotic stress induced oxidative stress in a rotifer Brachionus koreanus, an arc shell Scapharca broughtonii, and an intertidal flatworm Macrostomum lignano (An and Choi 2010; Lee et al. 2017; Rivera-Ingraham and Lignot 2017). In the flatworm, oxidative stress was associated with a dramatic increase of superoxide production at elevated salinity (Rivera-Ingraham and Lignot 2017). In a euryhaline intertidal crab S.serrata, hyperosmotic stress led to upregulation of antioxidants and an increase in H2O2 production; however, hypersaline exposure was also associated with hypoxia which made it difficult to separate the effects of osmotic stress and oxygen deficiency on mitochondrial ROS production (Paital and Chainy 2010, 2012). This indicates that similar to the thermal extremes, salinity extremes increase the rate of mitochondrial ROS production. However, the degree to which the mitochondrial ROS regulation, signaling, and oxidative stress are involved in osmotic tolerance of animals from highly stressful environments such as the intertidal zone, remains to be investigated. Mitochondrial responses to hypoxia and reoxygenation Intermittent hypoxia is a major stressor in intertidal habitats posing challenges to the mitochondrial machinery. Notably, studies in hypoxia-sensitive animal models (such as terrestrial mammals) show that mitochondria are a key target of hypoxia-reoxygenation stress (Kalogeris et al. 2014; Paradis et al. 2016). Oxygen deficiency suppresses activity of the mitochondrial ETS so that ATP synthesis decreases or ceases during severe hypoxia. This may result in ATP deficiency disrupting activity of cellular ATPases and interfering with the maintenance of the ion gradients in the cell (Hochachka and Lutz 2001). As mitochondria become depolarized in severe hypoxia, mitochondria FO, F1-ATPase reverts from an ATP producer to an ATP consumer further depleting the cellular ATP pool (St-Pierre et al. 2000). Paradoxically, the main damage to mitochondria of the sensitive species occurs during reoxygenation due to the burst of ROS generation caused by the electron slip from the highly reduced ETS intermediates (Kalogeris et al. 2014; Korge et al. 2015). The uncontrolled ROS generation may result in the oxidative injury leading to the mitochondrial membrane permeability transition, release of cytochrome c in the cytosol, and initiation of the apoptotic cascade, cell death, and organ failure (Kalogeris et al. 2014). Unlike mammalian mitochondria, the mitochondria of hypoxia-tolerant intertidal mollusks are resilient to hypoxia-reoxygenation stress and rapidly recover after hypoxic exposure. The effects of hypoxia on the mitochondrial function of intertidal mollusks are species-specific and depend on the degree of hypoxic stress. In eastern oysters (C. virginica), extreme hypoxia (6 days at near-anoxia) caused a decline in the ETS capacity and OXPHOS rate but did not affect the rates of the proton leak (Kurochkin et al. 2009; Ivanina et al. 2012). This resulted in a slight but significant reduction of mitochondrial coupling indicated by the lower respiratory control ratio. In the Pacific oyster C.gigas, moderate hypoxia (3–12 h at 1.7 mg L−1 O2) also led to a slight but significant reduction of OXPHOS flux (Sussarellu et al. 2013), while in an extremely hypoxia-tolerant hard shell clam, 18 h of near-anoxic exposure led to upregulation of the ETS capacity and the suppression of the OXPHOS flux (Ivanina et al. 2016). Suppression of the OXPHOS activity during hypoxia in hypoxia-tolerant mollusks may be an adaptive mechanism to prevent ATP wastage due to the reverse action of mitochondria FO, F1 ATPase (St-Pierre et al. 2000). During reoxygenation, mitochondria of the hypoxia-tolerant intertidal mollusks such as oysters and clams show a strong compensatory increase in the mitochondrial respiratory flux and ETS capacity (Kurochkin et al. 2009; Sussarellu et al. 2013; Ivanina et al. 2016). It is worth noting that in these experiments, the mitochondrial capacity of hypoxia-exposed bivalves was measured under the normoxic conditions so that the findings reflect hypoxia-induced change in the intrinsic capacities of the mitochondrial OXPHOS and ETS systems rather than a direct functional response of mitochondria to low oxygen (Kurochkin et al. 2009; Ivanina et al. 2012, 2016; Sussarellu et al. 2013). The mechanisms underlying the upregulation of the ETS capacity during intermittent hypoxia in intertidal mollusks are not yet known and require further investigation. Based on the observation that the upregulation of ETS capacity begins in hypoxia (when the protein synthesis is suppressed) and accelerates in the first hour of reoxygenation, it has been hypothesized that the candidate mechanisms involve allosteric modulation and/or post-translational modifications of existing mitochondrial proteins rather than de novo synthesis of mitochondrial enzymes in hypoxia-tolerant clams and oysters (Sussarellu et al. 2013; Ivanina et al. 2016). An increase in the mitochondrial ETS capacity may assist in the recovery from the hypoxia-induced energy deficiency and mitigate ROS production during reoxygenation by stimulating the forward ETS flux and reducing the electron slip in hypoxia-tolerant intertidal mollusks (Ivanina et al. 2016; Ivanina and Sokolova 2016). This mechanism may also contribute to covering of the so-called oxygen debt—a post-hypoxic increase in the basal maintenance costs reflecting the metabolic costs of reinstating cellular homeostasis (including resynthesis of ATP and energy reserves) commonly observed in hypoxia-tolerant invertebrates (Lewis et al. 2007; Vismann and Hagerman 2008; Kurochkin et al. 2009). In contrast to hypoxia-tolerant mollusks, mitochondrial ETS and OXPHOS capacity as well as the mitochondrial membrane potential collapsed during reoxygenation in hypoxia-sensitive scallops (Ivanina et al. 2016) closely resembling mitochondrial deterioration during hypoxia-reoxygenation stress in mammalian tissues (Kalogeris et al. 2014; Korge et al. 2015). The anticipatory increase in antioxidants in preparation for oxidative stress is common in animals from highly variable and stressful environments including intertidal invertebrates, hypoxia-tolerant fish, and desiccation- and freeze-tolerant aquatic and terrestrial organisms (Moreira et al. 2016). Upregulation of antioxidants has also been reported in hypoxia-tolerant intertidal mollusks such as oysters and hard clams but not in their hypoxia sensitive counterparts, the bay scallops (Ivanina et al. 2016; Ivanina and Sokolova 2016). Notably, upregulation rather than initially high baseline levels of antioxidants appears to be protective against the oxidative stress induced by the intermittent hypoxia in marine mollusks (Ivanina et al. 2016; Ivanina and Sokolova 2016). Furthermore, mitochondrial tolerance to fluctuating oxygen levels in oysters and hard clams was associated with the high activity of mitochondrial proteases that degrade oxidatively damaged proteins thereby maintaining the integrity of mitochondrial proteome (Ivanina and Sokolova 2016). In contrast, in hypoxia-sensitive scallops intermittent hypoxia suppressed the activity of ATP-dependent proteases, which went hand in hand with accumulation of oxidatively damaged proteins (Ivanina and Sokolova 2016). These data indicate that mitochondrial protein homeostasis and quality control mechanisms (including antioxidants and proteolytic systems) play an important role in mitochondrial tolerance to fluctuating oxygen levels of intertidal mollusks. Nitric oxide (NO) can also play a role in hypoxia tolerance of due to its cytoprotective effects and regulation of mitochondrial function during oxygen fluctuations (Lopez-Barneo et al. 2010). In the eastern oyster C. virginica, activity of NO synthase and NO content were suppressed during hypoxia and slowly restored (within 6–12 h) during reoxygenation (Ivanina et al. 2010). Lower NO content in oyster tissues may support higher OXPHOS flux during early stage (first hour) of post-hypoxic recovery, since NO was shown to inhibit OXPHOS activity in oyster mitochondria (Ivanina et al. 2010). To date, the physiological mechanisms and bioenergetic implications of NO regulation in hypoxia-tolerant intertidal animals are not well understood and require further investigation. Mitochondrial mechanisms of sulfide tolerance Oxygen deficiency in anoxic marine sediments is commonly associated with hydrogen sulfide (H2S) stress produced by the sulfur-reducing anaerobic bacteria. Hydrogen sulfide is a potent mitochondrial poison (Truong et al. 2006) that enhances anoxia-induced mortality in marine organisms (Vaquer-Sunyer and Duarte 2010). Some sulfide-tolerant animals (such as hydrothermal vent mussels, tubeworms, or lucinid clams) have evolved intracellular symbioses with sulfur-oxidizing bacteria that aid hosts in H2S detoxification and energy gain (Naganuma et al. 2005; Caro et al. 2009). However, mitochondria of intertidal and sediment-dwelling marine invertebrates also possess a marked tolerance to H2S toxicity and ability to detoxify H2S by converting it to thiosulfate (Doeller 1995; Parrino et al. 2000; Doeller et al. 2001; Kraus and Doeller 2004). Mitochondrial sulfide oxidation requires molecular oxygen that can be transported by bioirrigation (e.g., through animal burrows or molluscan siphons) from oxygenated bottom water into the depth of anoxic sediment. Notably, in sulfide-tolerant marine mollusks and annelids, the rates of the mitochondrial oxygen consumption with sulfide as an electron donor can reach up to 60–170% of that with a glycolytic substrate such as succinate (Powell and Somero 1986; Doeller 1995; Grieshaber and Volkel 1998; Parrino et al. 2000). Mitochondrial sulfide oxidation is coupled to ATP production at low sulfide levels and becomes progressively uncoupled as the sulfide concentrations rise, so that at high H2S concentrations the detoxification function predominates (Powell and Somero 1986; Doeller 1995; Grieshaber and Volkel 1998; Parrino et al. 2000). Rapid, ATP-coupled sulfide oxidation may reflect mitochondrial adaptation to high sulfidic habitats where elevated H2S levels in the sediment (up to 5 mM) may lead to accumulation of up to 100 µM of sulfide inside the cell (Doeller 1995; Doeller et al. 2001; Kraus and Doeller 2004). Interestingly, the capacity for mitochondrial sulfide oxidation coupled to ATP production may be an ancestral trait of eukaryotic mitochondria as it is found in distantly related organisms including mollusks, annelids, and fish (Grieshaber and Volkel 1998; Olson 2012) as well as in terrestrial vertebrates such as chickens and rats (albeit the rates of sulfide oxidation are considerably lower in terrestrial vertebrates compared to sulfide-tolerant invertebrates) (Yong and Searcy 2001). Besides sulfide detoxification mechanisms, mitochondria of some sulfide-tolerant benthic invertebrates express high activity of alternative oxidase (AOX), an ETS enzyme that can transfer electrons from coenzyme Q at the mitochondrial Q junction to oxygen bypassing Complexes III and IV of the mitochondrial ETS (Fig. 2;McDonald et al. 2009). This enzyme is found in most groups of invertebrates and lower chordates, as well as in fungi and plants but appears to be lost in arthropods and vertebrates (McDonald et al. 2009). It has been hypothesized that AOX activity serves as a safety valve to reduce production of ROS when cytochrome c oxidase (Complex IV) is inhibited by sulfide (Hahlbeck et al. 2000; Parrino et al. 2000; Tschischka et al. 2000). However, broad evolutionary distribution and functionality of AOX in different (including sulfide-sensitive) organisms indicate a broader regulatory role for AOX in stress tolerance, possibly as a buffer to counteract short-term metabolic fluctuations and maintain redox balance during stress (McDonald et al. 2009; Rasmusson et al. 2009). Effects of pH Mitochondria of intertidal mollusks (such as mussels Mytilus edulis and M.arenaria, and clams Mercenaria mercenaria) are sensitive to the shifts in pH and exhibit relatively narrow pH optima between 6.5 and 7.5 for the mitochondrial coupling (indicated by RCR) and 7.0 and 7.4 for the OXPHOS flux (Ballantyne and Storey 1983, 1984; Ballantyne and Moon 1985; Moyes et al. 1985). Bicarbonate which commonly accumulates in the molluscan cells along with the drop in pH (such as during the valve closure at the low tide or during exposure to environmental hypercapnia) further suppresses the mitochondrial respiration and OXPHOS rates as shown for the hard clam M. mercenaria and the bay scallop A. irradians (Haider et al. 2016). Notably, low pH (∼6.5) stimulates ROS production in M. mercenaria mitochondria, and this effect is not alleviated by bicarbonate despite mild uncoupling (Haider et al. 2016). In stress-tolerant intertidal mollusks including gastropods and bivalves, prolonged anaerobiosis may result in a strong decrease of the intracellular pH (from 7.6 down to 6.9) reflecting accumulation of acidic metabolic wastes (Grieshaber et al. 1994; Sokolova et al. 2000a, 2000b). Therefore, suppression of the mitochondrial activity caused by acidosis may aid in metabolic rate depression during prolonged air exposure or seasonal hypoxia/hypercapnia typical for eutrophicated coastal zones (Reipschläger and Pörtner 1996; Burnett 1997; Pörtner et al. 1998, 2005). The potential physiological significance of the mitochondrial suppression at high pH (>7.8) is less clear and requires further investigation. Responses to pollutants Unlike fluctuations of temperature, salinity, or oxygen that are common natural stressors in the intertidal zone, elevated concentrations of pollutants such as trace metals and organic toxins are relatively novel stressors introduced by human activities (Clark 2002). Therefore, unless mitochondrial adaptations to natural abiotic stressors lead to the cross-protective effects against pollutants, one might expect high sensitivity to anthropogenic pollutants in mitochondria of intertidal organisms. Indeed, studies in intertidal mollusks such as oysters C. virginica and clams M. mercenaria showed that their mitochondria are sensitive to trace metal pollutants such as cadmium (Cd2+) and copper (Cu2+) (Sokolova 2004; Sokolova et al. 2005b; Ivanina et al. 2012; Ivanina and Sokolova 2013). In oysters and clams, the mitochondrial OXPHOS rates as well as activities of key ETS enzymes are inhibited by low micromolar concentrations of Cd2+ (Sokolova 2004; Ivanina et al. 2008; Kurochkin et al. 2011) similar to the mitochondria of rats (Belyaeva et al. 2001, 2006, 2011). Mitochondrial sensitivity to Cd2+ is enhanced by elevated temperatures in intertidal bivalves (Sokolova 2004; Ivanina et al. 2008) and is in part mediated by oxidative damage to mitochondrial proteins and/or lipids (Cherkasov et al. 2007a; Sanni et al. 2008) as well as by the depletion of mitochondria during Cd exposure (Cherkasov et al. 2006a). Exposure to Cd also suppresses mitochondrial recovery after intermittent hypoxia in the eastern oyster C. virginica (Kurochkin et al. 2009; Ivanina et al. 2012). This indicates that Cd is not only directly toxic to mitochondria of intertidal mollusks but may also impact their ability to maintain mitochondrial integrity and function during emersion/immersion cycles. Copper (Cu2+) appears less toxic to the molluscan mitochondria than Cd2+ (Ivanina et al. 2013; Ivanina and Sokolova 2013) albeit the toxic mechanisms of both trace metals are similar (Valko et al. 2005). This may reflect better handling capacity of Cu by mollusks as reflected in the lower accumulated Cu burdens (compared with those of Cd) in the whole tissues and the mitochondria during metal exposures (Sokolova et al. 2005a; Hawkins and Sokolova 2017). Interestingly, low pH reduces the mitochondrial toxicity of Cd2+ and Cu2+ in oysters as well as clams indicating that mild acidosis may exert cytoprotective effects in polluted habitats (Ivanina and Sokolova 2013). Besides metals, mitochondria of aquatic organisms are susceptible to other environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), antibiotics, and pesticides as discussed in recent excellent reviews (Meyer et al. 2013; Jayasundara 2017). The mechanisms and environmental implications of the mitotoxicity of pollutants have not been extensively investigated in intertidal organisms. Future studies are needed to further elucidate the responses of organisms from highly stressful environments such as the intertidal zone to mitochondrial poisons (including metals, organic pollutants, metal-containing nanoparticles, and their mixtures) alone and in combination with other abiotic stressors. Outlook and future challenges Mitochondria of intertidal animals exhibit high tolerance to common environmental stressors in their habitats including temperature stress, fluctuations in osmolarity and ion concentrations, and intermittent hypoxia. A notable exception includes high sensitivity of mitochondria of intertidal mollusks to inhibition by pH shifts and may represent an adaptive mechanism to support stress-induced metabolic rate depression. Sensitivity of molluscan mitochondria to trace metals such as Cd2+ and Cu2+ likely indicates the lack of prior exposure to these recently introduced anthropogenic stressors and emphasizes that mitochondrial tolerance mechanisms are stressor-specific. Future studies are required to identify specific molecular targets responsible for the exceptional robustness of mitochondria from intertidal organisms to temperature, salinity, and hypoxia stress. Mitochondrial ETS is a promising target for identification of such mechanisms since ETS controls a large proportion (∼80–90%) of the OXPHOS capacity under the optimum as well as the stressful conditions (Dufour et al. 1996; Chamberlin 2004; Kurochkin et al. 2011; Ivanina et al. 2012). Interestingly, convergent evolution of key mitochondrial ETS complexes was implicated in aquatic–terrestrial transitions of in several molluscan lineages (Romero et al. 2016) and in adaptations to chronic hypoxia in mammals (Tian et al. 2017) emphasizing the key role of ETS adjustments in conquering the stressful environments. Therefore, investigation of the molecular diversity of ETS complexes in different environments as well as the epigenetic and post-translational mechanisms that regulate mitochondrial ETS capacity in animals from highly stressful environments are promising avenues for future discoveries. Mitochondrial proteostasis and redox homeostasis are another important contributor to mitochondrial stress tolerance of intertidal organisms (Ivanina et al. 2016; Ivanina and Sokolova 2016) requiring further investigations. To date, most studies of mitochondrial physiology of intertidal organisms have been focused on bioenergetics and oxidative stress. With the rapidly developing molecular tools that can be used in non-model organisms, the field is ripe to move beyond the mitochondrial bioenergetics and ROS and explore the ways in which mitochondrial metabolism, cell signaling, and immunity are coordinated to facilitate survival in stressful environments. Such underexplored yet potentially fruitful areas of future research include the potential roles of mitonuclear interactions in mitochondrial fitness under extreme stress and the role of mitochondrial dynamics (fusion, fission, proliferation, and mitophagy) in environmental stress adaptations. Furthermore, recent genomic studies demonstrate “stressome expansion,” i.e., proliferation of stress-related genes such as those encoding molecular chaperones and antioxidants in stress-tolerant intertidal mollusks such as Pacific oysters (Zhang et al. 2012). It would be intriguing to determine whether similar gene expansion has occurred in mitochondrial stressome of organisms adapted to the intertidal zone and other stressful environments. Comparisons of the mitochondrial physiological and molecular responses to stress in stress-tolerant intertidal species with those of stress-sensitive organisms including well-studied animal models (such as terrestrial mammals and insects) could help identify the physiological weak links responsible for the mitochondrial susceptibility to stress, discover the evolutionarily tested solutions to overcome these weaknesses, and might generate novel hypotheses for the strategies to mitigate mitochondrial stress in other systems (such as domestic animals and humans). Acknowledgments I thank the Society for Integrative and Comparative Biology (SICB), the Company of Biologists, and the National Science Foundation (award IOS-1738378 to Wendy Hood and Karine Salin) for travel support to the annual SICB meeting in San Francisco (2018), and the organizers and attendees of the “Inside the Black Box: The Mitochondrial Basis of Life-History Variation and Animal Performance” symposium for enthusiastic and productive discussions. The useful comments of three anonymous reviewers on an earlier draft are also gratefully acknowledged. Funding The work was in part supported by the Deutsche Forschungsgemeinschaft (DFG) in the framework of the Research Training Group “Baltic TRANSCOAST” (award number GRK 2000) and by the U.S. National Science Foundation, award IOS-1738378. This is Baltic TRANSCOAST Publication No. GRK2000/0012. References Abele D , Heise K , Pörtner HO , Puntarulo S. 2002 . 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ISSN: 1540-7063
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DOI: 10.1093/icb/icy017
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Abstract

Abstract Mitochondria are the key organelles involved in energy and redox homeostasis, cellular signaling, and survival. Animal mitochondria are exquisitely sensitive to environmental stress, and stress-induced changes in the mitochondrial integrity and function have major consequences for the organismal performance and fitness. Studies in the model organisms such as terrestrial mammals and insects showed that mitochondrial dysfunction is a major cause of injury during pathological conditions and environmental insults such as hypoxia, ischemia-reperfusion, and exposure to toxins. However, animals from highly stressful environments (such as the intertidal zone of the ocean) can maintain mitochondrial integrity and function despite intense and rapid fluctuations in abiotic conditions and associated changes in the intracellular milieu. Recent studies demonstrate that mitochondria of intertidal organisms (including mollusks, crustaceans, and fish) are capable of maintaining activity of mitochondrial electron transport system (ETS), ATP synthesis, and mitochondrial coupling in a broad range of temperature, osmolarity, and ion content. Mitochondria of intertidal organisms such as mollusks are also resistant to hypoxia-reoxygenation injury and show stability or even upregulation of the mitochondrial ETS activity and ATP synthesis capacity during intermittent hypoxia. In contrast, pH optima for mitochondrial ATP synthesis and respiration are relatively narrow in intertidal mollusks and may reflect adaptation to suppress metabolic rate during pH shifts caused by extreme stress. Sensitivity to anthropogenic pollutants (such as trace metals) in intertidal mollusks appears similar to that of other organisms (including mammals) and may reflect the lack of adaptation to these evolutionarily novel stressors. The mechanisms of the exceptional mitochondrial resilience to temperature, salinity, and hypoxic stress are not yet fully understood in intertidal organisms, yet recent studies demonstrate that they may involve rapid modulation of the ETS capacity (possibly due to post-translation modification of mitochondrial proteins), upregulation of antioxidant defenses in anticipation of oxidative stress, and high activity of mitochondrial proteases involved in degradation of damaged mitochondrial proteins. With rapidly developing molecular tools for non-model organisms, future studies of mitochondrial adaptations should pinpoint the molecular sites associated with the passive tolerance and/or active regulation of mitochondrial activity during stress exposures in intertidal organisms, investigate the roles of mitochondria in transduction of stress signals, and explore the interplay between bioenergetics and mitochondrial signaling in facilitating survival in these highly stressful environments. Mitochondria as the central hub of stress tolerance Mitochondria are the hallmark of eukaryotic life involved in all essential cellular processes (Lane 2005). They provide over 90% of cellular ATP in animals (with a few exceptions of obligate anaerobes) and serve as a cellular hub that connects energy metabolism, stress sensing, signaling, and cell survival (Lane 2005; Naquet et al. 2016; Monlun et al. 2017). Studies in model organisms such as terrestrial mammals and insects show that mitochondria are exquisitely sensitive to environmental stress and act both as a target of stress and the coordinating center for the adaptive cellular response (Fig. 1). Mitochondrial stress can impair the ATP supply of the cell and lead to oxidative injury if the mitochondrial production of reactive oxygen species (ROS) exceeds the capacity of cellular antioxidants to curb the damage (Vakifahmetoglu-Norberg et al. 2017). Studies in mammals also show that stressed mitochondria release important signaling molecules engaging pleiotropic cellular mechanisms to mitigate or repair the stress-induced damage (Bohovych and Khalimonchuk 2016; Naquet et al. 2016). Mitochondrially-produced metabolic intermediates can act as substrates for post-translation regulation of the enzymes through acetylation, succinylation, and phosphorylation (Naquet et al. 2016). In mammalian models, mitochondria also play a key role in the innate immunity through activation of signaling proteins, release of ROS, and other danger signals such as mitochondrial DNA (mtDNA) and cardiolipin (Monlun et al. 2017). Notably, some multifunctional mitochondrial proteins and mitochondria-derived stress signals regulate both oxidative phosphorylation (OXPHOS) and the immune response thus providing the molecular basis for the cross-talk between mitochondrial bioenergetics and stress defense (Lartigue and Faustin 2013; Monlun et al. 2017). While the complexity of the mitochondrial bioenergetic and signaling network is not yet fully understood, it is increasingly evident that maintenance of the mitochondrial integrity and mitochondrially-derived cellular signaling are critical for cellular homeostasis and survival (Lane 2005; Bohovych and Khalimonchuk 2016; Vakifahmetoglu-Norberg et al. 2017). If these mechanisms fail and cellular injury accumulates, mitochondria initiate programmed death pathways leading to elimination of the damaged cells and potentially culminating in organ failure and mortality (Vakifahmetoglu-Norberg et al. 2017). Fig. 1 View largeDownload slide The mitochondrial stress sensing and response cascade based on the studies of model systems such as rodents, Drosophila and mammalian cell lines. Mitochondrial stress commonly suppresses mitochondrial oxidative phosphorylation (OXPHOS) and activity of the electron transport chain (ETS), and elevates electron slip resulting in ROS production. These changes can result in the energy deficiency due to the mismatch between the cellular ATP demand and mitochondrial ATP generation and oxidative injury if the antioxidant system cannot cope with the increased ROS production. Mitochondrial stress results in the release of important second messengers and stress signals such as ROS and Ca2+, which regulate the cellular signaling cascades including the hypoxia-inducible factor 1 (HIF-1), AMP kinase, and other stress-responsive kinases that ultimately lead to upregulation of the antioxidant defense, ATP synthesis, and nutrient recycling through autophagy. Furthermore, mtDNA and cardiolipin act as danger-associated molecular patterns (DAMPs) that along with other mitochondrial signals such as MAVS regulate immune response and inflammation. Mitochondrially-produced metabolites can also serve as substrates for post-translational modifications (phosphorylation, succinylation, and acetylation) of proteins that regulate the cellular homeostasis and metabolic flux. When successful, the protective mitochondrially-driven responses assist in reinstating the cellular homeostasis. However, excessive mitochondrial stress or failure of the adaptive response results in unmitigated mitochondrial damage and release of the apoptotic signals triggering cell death. Fig. 1 View largeDownload slide The mitochondrial stress sensing and response cascade based on the studies of model systems such as rodents, Drosophila and mammalian cell lines. Mitochondrial stress commonly suppresses mitochondrial oxidative phosphorylation (OXPHOS) and activity of the electron transport chain (ETS), and elevates electron slip resulting in ROS production. These changes can result in the energy deficiency due to the mismatch between the cellular ATP demand and mitochondrial ATP generation and oxidative injury if the antioxidant system cannot cope with the increased ROS production. Mitochondrial stress results in the release of important second messengers and stress signals such as ROS and Ca2+, which regulate the cellular signaling cascades including the hypoxia-inducible factor 1 (HIF-1), AMP kinase, and other stress-responsive kinases that ultimately lead to upregulation of the antioxidant defense, ATP synthesis, and nutrient recycling through autophagy. Furthermore, mtDNA and cardiolipin act as danger-associated molecular patterns (DAMPs) that along with other mitochondrial signals such as MAVS regulate immune response and inflammation. Mitochondrially-produced metabolites can also serve as substrates for post-translational modifications (phosphorylation, succinylation, and acetylation) of proteins that regulate the cellular homeostasis and metabolic flux. When successful, the protective mitochondrially-driven responses assist in reinstating the cellular homeostasis. However, excessive mitochondrial stress or failure of the adaptive response results in unmitigated mitochondrial damage and release of the apoptotic signals triggering cell death. Exposure to environmental stressors such as heat or cold shock, osmotic stress, toxins, or lack of oxygen can shift the mitochondrial balancing act from the adaptive response to cell death due to the energy deficiency and/or the overwhelming mitochondrial or cellular damage (Fig. 1) (Bohovych and Khalimonchuk 2016; Vakifahmetoglu-Norberg et al. 2017). However, many eukaryotes (such as the inhabitants of the intertidal zones of the seas) are capable of surviving and maintaining mitochondrial homeostasis despite the frequent and drastic fluctuations in environmental conditions. Intertidal zone with its alternating periods of immersion and emersion, extreme fluctuations of temperature, salinity, pH, hydrodynamic forces, and desiccation stress is one of the most stressful environments for metazoan life (Helmuth et al. 2002; Richards 2011; Jensen and Denny 2016). Oxygen concentrations in the intertidal rock pools can fluctuate from near anoxia to hyperoxia (∼300–400% air saturation) over a daily cycle, and desiccation avoidance behaviors (such as shell closure during the low tide) may cause hypoxia and anoxia by limiting the gas exchange (Stephenson et al. 1934; Truchot and Duhamel-Jouve 1980; Kurochkin et al. 2009). Oxygen fluctuations are typically accompanied by the major fluctuations of pH and CO2 levels (Stephenson et al. 1934; Truchot and Duhamel-Jouve 1980). Temperature in intertidal habitats can change by 10–30° within a few hours reaching values in excess of 35–40°C during summer low tides (Sokolova and Boulding 2004; Cherkasov et al. 2007b; Helmuth et al. 2016). Furthermore, salinity may rapidly and dramatically fluctuate due to the evaporation and precipitation events. These changes pose major challenges to homeostatic mechanisms of intertidal organisms, especially those that have limited capacity for regulating the internal milieu such as body temperature, osmolarity, pH, or ionic concentration of the body fluids. In these organisms (including many intertidal invertebrates), the mitochondrial function must be maintained despite fluctuating intracellular conditions and restored after major physiological disruptions such as extreme temperatures or prolonged lack of oxygen. Marine mollusks belong to the ecologically dominant organisms in the intertidal zone and have successfully adapted to harsh life between the tides, representing an excellent model system to investigate mitochondrial adaptations to stress. Metabolic adaptations of intertidal mollusks have been extensively studied, and metabolic rate depression has emerged as a major adaptive mechanism to extreme stress (Guppy et al. 1994; Storey 2002; Sokolova et al. 2011). It involves a coordinated suppression of ATP consumption and production to conserve energy reserves, reduce accumulation of metabolic wastes, and support the membrane integrity and ion homeostasis at the expense of the less essential processes (Hochachka et al. 1996). If aerobic ATP production decreases due to the mitochondrial failure or lack of oxygen, it can be supplemented and/or replaced by anaerobic pathways (Sommer et al. 1997; Sommer and Pörtner 1999; Sokolova and Pörtner 2003; Bagwe et al. 2015). Notably, many stress-tolerant intertidal invertebrates evolved efficient anaerobic glycolytic pathways with higher yield of ATP, less metabolic protons, and volatile end products that can be released from the body to mitigate toxicity (Hochachka and Mommsen 1983; Sokolova et al. 2011). Furthermore, stress-tolerant intertidal organisms typically have high levels of glycolytic substrates and tissue buffering capacity to prevent excessive cellular acidosis due to anaerobiosis (Eberlee and Storey 1984; Sokolova et al. 2000b). Together, these metabolic adjustments allow intertidal organisms to survive without oxygen, food, or water for days to months, depending on the environmental temperature (Hochachka and Lutz 2001; Rebecchi et al. 2007). While regulation of energy metabolism is recognized for its central role in adaptations to environmental stress in the intertidal zone, an important piece of the overall puzzle is still lacking—namely, understanding how the mitochondrial function is regulated to sustain energy metabolism and prevent cellular damage during extreme stress. Here I provide an overview of mitochondrial responses of intertidal organisms to environmental stressors (including temperature, salinity, hypoxia, pH, and trace metals) focusing on the functional traits relevant to ATP generation, mitochondrial efficiency, and cellular redox balance (Table 1 and Fig. 2), discuss the potential roles of mitochondrial resistance for environmental stress tolerance, and identify important gaps in our knowledge of mitochondrial physiology of intertidal animals that warrant further investigation. Table 1 Terminology and common approaches used to assess bioenergetics-related traits in mitochondria of intertidal organisms discussed in this review Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production a In different studies, OXPHOS, LEAK, and ETS fluxes are assessed with NADH-linked substrates such as pyruvate or glutamate (activating Complexes I, III, and IV), FADH2-linked substrates such as succinate (activating Complexes II, III, and IV), or a mixture of NADH- and FADH2-linked substrates that fully activate ETS flux. Table 1 Terminology and common approaches used to assess bioenergetics-related traits in mitochondria of intertidal organisms discussed in this review Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production Mitochondrial trait Alternative names Functional significance Measured as: OXPHOS flux State 3, ADP-stimulated respiration The maximal OXPHOS activity reflective of the ATP synthesis capacity Oxygen consumption of mitochondria with saturating concentrations of substratesa and ADP and at high ADP/ATP ratios LEAK rate State 4, State4+, State4ol, proton leak rate Short-circuit H+ fluxes reflective of all futile proton and cation cycles that dissipate protonmotive force (Δp) without the concomitant ATP synthesis Oxygen consumption of mitochondria with saturating concentrations of substratesa at low ADP/ATP ratios when ADP has been exhausted and/or mitochondrial FO, F1 ATPase inhibited (e.g., by oligomycin) ETS flux Uncoupled or non-coupled respiration rate Maximum activity of the ETS system Oxygen consumption of mitochondria with saturating concentrations of substratesa in the presence of protonophores to collapse Δp Respiratory control ratio RCR Measure of mitochondrial coupling Calculated as a ratio of OXPHOS to LEAK flux (or State 3 to State 4 rate) ROS production Electron slip in the ETS resulting in production of superoxide Chemical reporters sensitive to superoxide, H2O2, or hydroxyl radical; electron spin resonance Oxidative stress Mismatch between the ROS production and the cellular capacity to detoxify ROS Proxies such as accumulation of oxidation products of proteins, lipids, and DNA; upregulation of antioxidant defenses; or elevated ROS production a In different studies, OXPHOS, LEAK, and ETS fluxes are assessed with NADH-linked substrates such as pyruvate or glutamate (activating Complexes I, III, and IV), FADH2-linked substrates such as succinate (activating Complexes II, III, and IV), or a mixture of NADH- and FADH2-linked substrates that fully activate ETS flux. Fig. 2 View largeDownload slide Schematic representation of the common bioenergetic-related functions assessed in mitochondria. (A) Complexes I and II of the mitochondrial electron transport system (ETS) transfer electrons from NADH-linked (e.g., pyruvate) or FADH2-linked (e.g., succinate) substrates, respectively, to coenzyme Q junction (Q). The electrons from coenzyme Q are further transferred via Complex III to cytochrome c oxidase (Complex IV) of the ETS, which reduces oxygen to water. Free energy released during the electron transport is used by Complexes I, III, and IV to pump protons from the mitochondrial matrix into the intermembrane space of the mitochondria thereby creating the electrochemical proton gradient across the inner mitochondrial membrane. The energy conserved in this gradient is used to drive the ATP synthesis as the protons flow through the mitochondrial FO, F1-ATPase back into the matrix. Thereby, creation of the proton gradient by ETS and its dissipation by FO, F1-ATPase serve as a mechanism that couples oxidation of energy-rich organic substrates to ATP generation. Joint activities of ETS and FO, F1-ATPase represent mitochondrial oxidative phosphorylation (OXPHOS). Some of the protons, however, may leak back into the mitochondrial matrix bypassing FO, F1-ATPase thereby dissipating the mitochondrial proton gradient without the concomitant ATP production (LEAK). Electrons may slip from the ETS complexes (in particular, Complexes I and III) onto oxygen (not shown) resulting in the incomplete reduction of oxygen to superoxide and initiating the cascade of ROS production. (B) Mitochondrial coupling efficiency depends on the interplay between the processes that create and dissipate the proton motive force (Δp, the electrochemical, and pH gradient across the inner mitochondrial membrane). Substrate oxidation subsystem (including tricarboxylic acid cycle, substrate transporters, and ETS) generates Δp (empty arrow), whereas phosphorylation subsystem and proton leak dissipate Δp (filled arrows). Fig. 2 View largeDownload slide Schematic representation of the common bioenergetic-related functions assessed in mitochondria. (A) Complexes I and II of the mitochondrial electron transport system (ETS) transfer electrons from NADH-linked (e.g., pyruvate) or FADH2-linked (e.g., succinate) substrates, respectively, to coenzyme Q junction (Q). The electrons from coenzyme Q are further transferred via Complex III to cytochrome c oxidase (Complex IV) of the ETS, which reduces oxygen to water. Free energy released during the electron transport is used by Complexes I, III, and IV to pump protons from the mitochondrial matrix into the intermembrane space of the mitochondria thereby creating the electrochemical proton gradient across the inner mitochondrial membrane. The energy conserved in this gradient is used to drive the ATP synthesis as the protons flow through the mitochondrial FO, F1-ATPase back into the matrix. Thereby, creation of the proton gradient by ETS and its dissipation by FO, F1-ATPase serve as a mechanism that couples oxidation of energy-rich organic substrates to ATP generation. Joint activities of ETS and FO, F1-ATPase represent mitochondrial oxidative phosphorylation (OXPHOS). Some of the protons, however, may leak back into the mitochondrial matrix bypassing FO, F1-ATPase thereby dissipating the mitochondrial proton gradient without the concomitant ATP production (LEAK). Electrons may slip from the ETS complexes (in particular, Complexes I and III) onto oxygen (not shown) resulting in the incomplete reduction of oxygen to superoxide and initiating the cascade of ROS production. (B) Mitochondrial coupling efficiency depends on the interplay between the processes that create and dissipate the proton motive force (Δp, the electrochemical, and pH gradient across the inner mitochondrial membrane). Substrate oxidation subsystem (including tricarboxylic acid cycle, substrate transporters, and ETS) generates Δp (empty arrow), whereas phosphorylation subsystem and proton leak dissipate Δp (filled arrows). Mitochondrial responses to temperature Intertidal organisms including invertebrates and fish display high thermal tolerance of mitochondrial functions and broad phenotypic plasticity of mitochondrial metabolism during thermal acclimation (Dahlhoff and Somero 1993; Cherkasov et al. 2010; Hilton et al. 2010). Thus, mitochondria of an intertidal triplefin fish (Bellapiscis medius) were able to maintain higher OXPHOS flux and ETS activity as well as better coupling (indicated by higher RCR) at elevated temperature (30°C) compared with two sympatric subtidal species (Forsterygion varium and F. malcolmi) (Hilton et al. 2010). Temperature tolerance threshold for the mitochondrial OXPHOS or ETS activity (assessed as the Arrhenius breakpoint temperature [ABT] beyond which the respective mitochondrial function is inhibited or disrupted) is also higher in intertidal organisms compared with their subtidal counterparts. Thus, the ABT for the mitochondrial ETS activity was 38–44°C in intertidal (green, red, and pink) abalone, depending on the acclimation temperature (5–23°C) and increased by 0.5–0.6°C per 1°C rise in the acclimation temperature (Dahlhoff and Somero 1993). In contrast, the ABT for the mitochondrial ETS activity of a subtidal (pinto) abalone was considerably lower (32–35°C) and did not show an adaptive upward shift with warm acclimation (Dahlhoff and Somero 1993). The ABT for OXPHOS rate in mitochondria of an intertidal mud crab Scylla serrata was ∼37°C, and the mitochondria could maintain a stable rate of ATP generation between 25°C and 37°C (Paital and Chainy 2014). A significant drop in OXPHOS rate and the loss of coupling were found only at 40°C in the mud crab (Paital and Chainy 2014). High thermal tolerance of mitochondrial functions in intertidal species likely represents a safety margin that permits these organisms to survive periodic thermal extremes (up to 35–40°C) during the summer low tides (Sokolova and Boulding 2004; Cherkasov et al. 2007b; Helmuth et al. 2016). While the thermal tolerance thresholds for mitochondrial activity are shifted to higher levels in intertidal organisms, the mechanisms of temperature-induced mitochondrial disruption appear to be similar in eurythermal and stenothermal species of invertebrates. Generally, elevated temperature stress results in the reduced mitochondrial coupling (shown by lower RCR) and excess ROS generation as shown in intertidal bivalves Crassostrea virginica and Mya arenaria (Abele et al. 2002; Sokolova 2004; Cherkasov et al. 2006a, 2007a, 2010), a lugworm Arenicola marina (Keller et al. 2004), and a mud crab S. serrata (Paital and Chainy 2014). A similar pattern of reduced mitochondrial coupling and elevated ROS production (albeit occurring as a lower temperature) was found during warming in mitochondria of stenothermal bivalves such as an Antarctic clam Laternula elliptica (Abele et al. 2002; Peck et al. 2002; Heise et al. 2003). In these organisms, reduced mitochondrial coupling at elevated temperature reflects higher thermal sensitivity of the proton leak compared with the OXPHOS rate (Peck et al. 2002; Keller et al. 2004; Sokolova 2004; Cherkasov et al. 2006a, 2006b; Paital and Chainy 2014). Mild mitochondrial uncoupling during warming due to the elevated proton leak (that dissipates the protonmotive force Δp) may partially alleviate the ROS production which increases exponentially with increasing Δp (Miwa and Brand 2003). Interestingly, extreme temperatures (4°C and 42°C) also lead to the reduced mitochondrial coupling and relatively high mitochondrial proton leak in mammalian cells (Lemieux et al. 2017; Mitov et al. 2017). This indicates that the differential thermal sensitivity of the mitochondrial OXPHOS and proton leak may be common in animal mitochondria and not restricted to ectotherms. Changes in the mitochondrial density have also been implicated in adaptive metabolic responses to temperature in aquatic ectotherms. Typically, acclimation or adaptation to colder temperatures results in a compensatory increase of the mitochondrial density as shown in marine invertebrates and fish from different latitudes (Johnston et al. 1998; Sommer and Pörtner 2002; Cherkasov et al. 2010). Seasonal acclimatization also results in elevated mitochondrial content in winter and lower mitochondrial density in summer as was shown in intertidal mollusks C. virginica (Cherkasov et al. 2010) and lugworms A. marina (Sommer and Pörtner 2004). Mitochondrial proliferation in the cold may assist in the metabolic compensation by maintaining ATP production at lower temperatures and reducing diffusion distance for oxygen in the cell (Tyler and Sidell 1984; Londraville and Sidell 1990). Alternatively, a decrease in the mitochondrial density in summer may minimize the maintenance costs due to the increased mitochondrial proton leak at high temperatures (Peck et al. 2002; Keller et al. 2004). Effects of osmolarity and ion content Mitochondria of intertidal mollusks such as clams, oysters, and mussels are highly tolerant to the shifts in osmolarity and ionic strength of the media, with the optima for OXPHOS and mitochondrial coupling spanning the breadth of 400–500 mOsm around the species-specific optimum (Ballantyne and Storey 1983, 1984; Ballantyne and Moon 1985; Ballantyne and Moyes 1987a, 1987b, 1987c). Furthermore, mitochondria of intertidal and estuarine mollusks possess considerable plasticity and can adjust their osmotic optima during acclimation and acclimatization. Thus, acute hypoosmotic stress (150 mOsm, ∼300 mOsm below the acclimation osmolarity) led to a suppressed coupling, OXPHOS and COX capacity in gill mitochondria of a soft-shell clam M.arenaria, but this effect was fully reversed and the mitochondrial function restored after acclimation to low (150 mOsm) or fluctuating (150–450 mOsm) salinity (Haider et al. 2017). Acclimation to lower salinity also shifted the osmotic optima for mitochondrial OXPHOS and coupling in the gills of the eastern oysters C. virginica (Ballantyne and Moyes 1987a). Notably, compatible osmolytes such as taurine that accumulate in the molluscan cells during salinity shifts may also play an important role in mitochondria adjustments by exerting mitoprotective effects at high osmolarity, as shown in the Pacific oyster Crassostrea gigas (Sokolov and Sokolova 2018). Taken together, these data indicate that the mitochondria of intertidal mollusks are osmotically robust, plastic, and can maintain the bioenergetic capacity despite the salinity shifts. This likely reflects adaptations of the mitochondrial machinery to osmoconformity which results in shifts of intracellular osmolarity to match the ambient salinity. The mitochondria-dependent redox signaling and oxidative stress during the osmotic shifts remains a relatively unexplored area of mitochondrial physiology. Hyperosmotic stress induced oxidative stress in a rotifer Brachionus koreanus, an arc shell Scapharca broughtonii, and an intertidal flatworm Macrostomum lignano (An and Choi 2010; Lee et al. 2017; Rivera-Ingraham and Lignot 2017). In the flatworm, oxidative stress was associated with a dramatic increase of superoxide production at elevated salinity (Rivera-Ingraham and Lignot 2017). In a euryhaline intertidal crab S.serrata, hyperosmotic stress led to upregulation of antioxidants and an increase in H2O2 production; however, hypersaline exposure was also associated with hypoxia which made it difficult to separate the effects of osmotic stress and oxygen deficiency on mitochondrial ROS production (Paital and Chainy 2010, 2012). This indicates that similar to the thermal extremes, salinity extremes increase the rate of mitochondrial ROS production. However, the degree to which the mitochondrial ROS regulation, signaling, and oxidative stress are involved in osmotic tolerance of animals from highly stressful environments such as the intertidal zone, remains to be investigated. Mitochondrial responses to hypoxia and reoxygenation Intermittent hypoxia is a major stressor in intertidal habitats posing challenges to the mitochondrial machinery. Notably, studies in hypoxia-sensitive animal models (such as terrestrial mammals) show that mitochondria are a key target of hypoxia-reoxygenation stress (Kalogeris et al. 2014; Paradis et al. 2016). Oxygen deficiency suppresses activity of the mitochondrial ETS so that ATP synthesis decreases or ceases during severe hypoxia. This may result in ATP deficiency disrupting activity of cellular ATPases and interfering with the maintenance of the ion gradients in the cell (Hochachka and Lutz 2001). As mitochondria become depolarized in severe hypoxia, mitochondria FO, F1-ATPase reverts from an ATP producer to an ATP consumer further depleting the cellular ATP pool (St-Pierre et al. 2000). Paradoxically, the main damage to mitochondria of the sensitive species occurs during reoxygenation due to the burst of ROS generation caused by the electron slip from the highly reduced ETS intermediates (Kalogeris et al. 2014; Korge et al. 2015). The uncontrolled ROS generation may result in the oxidative injury leading to the mitochondrial membrane permeability transition, release of cytochrome c in the cytosol, and initiation of the apoptotic cascade, cell death, and organ failure (Kalogeris et al. 2014). Unlike mammalian mitochondria, the mitochondria of hypoxia-tolerant intertidal mollusks are resilient to hypoxia-reoxygenation stress and rapidly recover after hypoxic exposure. The effects of hypoxia on the mitochondrial function of intertidal mollusks are species-specific and depend on the degree of hypoxic stress. In eastern oysters (C. virginica), extreme hypoxia (6 days at near-anoxia) caused a decline in the ETS capacity and OXPHOS rate but did not affect the rates of the proton leak (Kurochkin et al. 2009; Ivanina et al. 2012). This resulted in a slight but significant reduction of mitochondrial coupling indicated by the lower respiratory control ratio. In the Pacific oyster C.gigas, moderate hypoxia (3–12 h at 1.7 mg L−1 O2) also led to a slight but significant reduction of OXPHOS flux (Sussarellu et al. 2013), while in an extremely hypoxia-tolerant hard shell clam, 18 h of near-anoxic exposure led to upregulation of the ETS capacity and the suppression of the OXPHOS flux (Ivanina et al. 2016). Suppression of the OXPHOS activity during hypoxia in hypoxia-tolerant mollusks may be an adaptive mechanism to prevent ATP wastage due to the reverse action of mitochondria FO, F1 ATPase (St-Pierre et al. 2000). During reoxygenation, mitochondria of the hypoxia-tolerant intertidal mollusks such as oysters and clams show a strong compensatory increase in the mitochondrial respiratory flux and ETS capacity (Kurochkin et al. 2009; Sussarellu et al. 2013; Ivanina et al. 2016). It is worth noting that in these experiments, the mitochondrial capacity of hypoxia-exposed bivalves was measured under the normoxic conditions so that the findings reflect hypoxia-induced change in the intrinsic capacities of the mitochondrial OXPHOS and ETS systems rather than a direct functional response of mitochondria to low oxygen (Kurochkin et al. 2009; Ivanina et al. 2012, 2016; Sussarellu et al. 2013). The mechanisms underlying the upregulation of the ETS capacity during intermittent hypoxia in intertidal mollusks are not yet known and require further investigation. Based on the observation that the upregulation of ETS capacity begins in hypoxia (when the protein synthesis is suppressed) and accelerates in the first hour of reoxygenation, it has been hypothesized that the candidate mechanisms involve allosteric modulation and/or post-translational modifications of existing mitochondrial proteins rather than de novo synthesis of mitochondrial enzymes in hypoxia-tolerant clams and oysters (Sussarellu et al. 2013; Ivanina et al. 2016). An increase in the mitochondrial ETS capacity may assist in the recovery from the hypoxia-induced energy deficiency and mitigate ROS production during reoxygenation by stimulating the forward ETS flux and reducing the electron slip in hypoxia-tolerant intertidal mollusks (Ivanina et al. 2016; Ivanina and Sokolova 2016). This mechanism may also contribute to covering of the so-called oxygen debt—a post-hypoxic increase in the basal maintenance costs reflecting the metabolic costs of reinstating cellular homeostasis (including resynthesis of ATP and energy reserves) commonly observed in hypoxia-tolerant invertebrates (Lewis et al. 2007; Vismann and Hagerman 2008; Kurochkin et al. 2009). In contrast to hypoxia-tolerant mollusks, mitochondrial ETS and OXPHOS capacity as well as the mitochondrial membrane potential collapsed during reoxygenation in hypoxia-sensitive scallops (Ivanina et al. 2016) closely resembling mitochondrial deterioration during hypoxia-reoxygenation stress in mammalian tissues (Kalogeris et al. 2014; Korge et al. 2015). The anticipatory increase in antioxidants in preparation for oxidative stress is common in animals from highly variable and stressful environments including intertidal invertebrates, hypoxia-tolerant fish, and desiccation- and freeze-tolerant aquatic and terrestrial organisms (Moreira et al. 2016). Upregulation of antioxidants has also been reported in hypoxia-tolerant intertidal mollusks such as oysters and hard clams but not in their hypoxia sensitive counterparts, the bay scallops (Ivanina et al. 2016; Ivanina and Sokolova 2016). Notably, upregulation rather than initially high baseline levels of antioxidants appears to be protective against the oxidative stress induced by the intermittent hypoxia in marine mollusks (Ivanina et al. 2016; Ivanina and Sokolova 2016). Furthermore, mitochondrial tolerance to fluctuating oxygen levels in oysters and hard clams was associated with the high activity of mitochondrial proteases that degrade oxidatively damaged proteins thereby maintaining the integrity of mitochondrial proteome (Ivanina and Sokolova 2016). In contrast, in hypoxia-sensitive scallops intermittent hypoxia suppressed the activity of ATP-dependent proteases, which went hand in hand with accumulation of oxidatively damaged proteins (Ivanina and Sokolova 2016). These data indicate that mitochondrial protein homeostasis and quality control mechanisms (including antioxidants and proteolytic systems) play an important role in mitochondrial tolerance to fluctuating oxygen levels of intertidal mollusks. Nitric oxide (NO) can also play a role in hypoxia tolerance of due to its cytoprotective effects and regulation of mitochondrial function during oxygen fluctuations (Lopez-Barneo et al. 2010). In the eastern oyster C. virginica, activity of NO synthase and NO content were suppressed during hypoxia and slowly restored (within 6–12 h) during reoxygenation (Ivanina et al. 2010). Lower NO content in oyster tissues may support higher OXPHOS flux during early stage (first hour) of post-hypoxic recovery, since NO was shown to inhibit OXPHOS activity in oyster mitochondria (Ivanina et al. 2010). To date, the physiological mechanisms and bioenergetic implications of NO regulation in hypoxia-tolerant intertidal animals are not well understood and require further investigation. Mitochondrial mechanisms of sulfide tolerance Oxygen deficiency in anoxic marine sediments is commonly associated with hydrogen sulfide (H2S) stress produced by the sulfur-reducing anaerobic bacteria. Hydrogen sulfide is a potent mitochondrial poison (Truong et al. 2006) that enhances anoxia-induced mortality in marine organisms (Vaquer-Sunyer and Duarte 2010). Some sulfide-tolerant animals (such as hydrothermal vent mussels, tubeworms, or lucinid clams) have evolved intracellular symbioses with sulfur-oxidizing bacteria that aid hosts in H2S detoxification and energy gain (Naganuma et al. 2005; Caro et al. 2009). However, mitochondria of intertidal and sediment-dwelling marine invertebrates also possess a marked tolerance to H2S toxicity and ability to detoxify H2S by converting it to thiosulfate (Doeller 1995; Parrino et al. 2000; Doeller et al. 2001; Kraus and Doeller 2004). Mitochondrial sulfide oxidation requires molecular oxygen that can be transported by bioirrigation (e.g., through animal burrows or molluscan siphons) from oxygenated bottom water into the depth of anoxic sediment. Notably, in sulfide-tolerant marine mollusks and annelids, the rates of the mitochondrial oxygen consumption with sulfide as an electron donor can reach up to 60–170% of that with a glycolytic substrate such as succinate (Powell and Somero 1986; Doeller 1995; Grieshaber and Volkel 1998; Parrino et al. 2000). Mitochondrial sulfide oxidation is coupled to ATP production at low sulfide levels and becomes progressively uncoupled as the sulfide concentrations rise, so that at high H2S concentrations the detoxification function predominates (Powell and Somero 1986; Doeller 1995; Grieshaber and Volkel 1998; Parrino et al. 2000). Rapid, ATP-coupled sulfide oxidation may reflect mitochondrial adaptation to high sulfidic habitats where elevated H2S levels in the sediment (up to 5 mM) may lead to accumulation of up to 100 µM of sulfide inside the cell (Doeller 1995; Doeller et al. 2001; Kraus and Doeller 2004). Interestingly, the capacity for mitochondrial sulfide oxidation coupled to ATP production may be an ancestral trait of eukaryotic mitochondria as it is found in distantly related organisms including mollusks, annelids, and fish (Grieshaber and Volkel 1998; Olson 2012) as well as in terrestrial vertebrates such as chickens and rats (albeit the rates of sulfide oxidation are considerably lower in terrestrial vertebrates compared to sulfide-tolerant invertebrates) (Yong and Searcy 2001). Besides sulfide detoxification mechanisms, mitochondria of some sulfide-tolerant benthic invertebrates express high activity of alternative oxidase (AOX), an ETS enzyme that can transfer electrons from coenzyme Q at the mitochondrial Q junction to oxygen bypassing Complexes III and IV of the mitochondrial ETS (Fig. 2;McDonald et al. 2009). This enzyme is found in most groups of invertebrates and lower chordates, as well as in fungi and plants but appears to be lost in arthropods and vertebrates (McDonald et al. 2009). It has been hypothesized that AOX activity serves as a safety valve to reduce production of ROS when cytochrome c oxidase (Complex IV) is inhibited by sulfide (Hahlbeck et al. 2000; Parrino et al. 2000; Tschischka et al. 2000). However, broad evolutionary distribution and functionality of AOX in different (including sulfide-sensitive) organisms indicate a broader regulatory role for AOX in stress tolerance, possibly as a buffer to counteract short-term metabolic fluctuations and maintain redox balance during stress (McDonald et al. 2009; Rasmusson et al. 2009). Effects of pH Mitochondria of intertidal mollusks (such as mussels Mytilus edulis and M.arenaria, and clams Mercenaria mercenaria) are sensitive to the shifts in pH and exhibit relatively narrow pH optima between 6.5 and 7.5 for the mitochondrial coupling (indicated by RCR) and 7.0 and 7.4 for the OXPHOS flux (Ballantyne and Storey 1983, 1984; Ballantyne and Moon 1985; Moyes et al. 1985). Bicarbonate which commonly accumulates in the molluscan cells along with the drop in pH (such as during the valve closure at the low tide or during exposure to environmental hypercapnia) further suppresses the mitochondrial respiration and OXPHOS rates as shown for the hard clam M. mercenaria and the bay scallop A. irradians (Haider et al. 2016). Notably, low pH (∼6.5) stimulates ROS production in M. mercenaria mitochondria, and this effect is not alleviated by bicarbonate despite mild uncoupling (Haider et al. 2016). In stress-tolerant intertidal mollusks including gastropods and bivalves, prolonged anaerobiosis may result in a strong decrease of the intracellular pH (from 7.6 down to 6.9) reflecting accumulation of acidic metabolic wastes (Grieshaber et al. 1994; Sokolova et al. 2000a, 2000b). Therefore, suppression of the mitochondrial activity caused by acidosis may aid in metabolic rate depression during prolonged air exposure or seasonal hypoxia/hypercapnia typical for eutrophicated coastal zones (Reipschläger and Pörtner 1996; Burnett 1997; Pörtner et al. 1998, 2005). The potential physiological significance of the mitochondrial suppression at high pH (>7.8) is less clear and requires further investigation. Responses to pollutants Unlike fluctuations of temperature, salinity, or oxygen that are common natural stressors in the intertidal zone, elevated concentrations of pollutants such as trace metals and organic toxins are relatively novel stressors introduced by human activities (Clark 2002). Therefore, unless mitochondrial adaptations to natural abiotic stressors lead to the cross-protective effects against pollutants, one might expect high sensitivity to anthropogenic pollutants in mitochondria of intertidal organisms. Indeed, studies in intertidal mollusks such as oysters C. virginica and clams M. mercenaria showed that their mitochondria are sensitive to trace metal pollutants such as cadmium (Cd2+) and copper (Cu2+) (Sokolova 2004; Sokolova et al. 2005b; Ivanina et al. 2012; Ivanina and Sokolova 2013). In oysters and clams, the mitochondrial OXPHOS rates as well as activities of key ETS enzymes are inhibited by low micromolar concentrations of Cd2+ (Sokolova 2004; Ivanina et al. 2008; Kurochkin et al. 2011) similar to the mitochondria of rats (Belyaeva et al. 2001, 2006, 2011). Mitochondrial sensitivity to Cd2+ is enhanced by elevated temperatures in intertidal bivalves (Sokolova 2004; Ivanina et al. 2008) and is in part mediated by oxidative damage to mitochondrial proteins and/or lipids (Cherkasov et al. 2007a; Sanni et al. 2008) as well as by the depletion of mitochondria during Cd exposure (Cherkasov et al. 2006a). Exposure to Cd also suppresses mitochondrial recovery after intermittent hypoxia in the eastern oyster C. virginica (Kurochkin et al. 2009; Ivanina et al. 2012). This indicates that Cd is not only directly toxic to mitochondria of intertidal mollusks but may also impact their ability to maintain mitochondrial integrity and function during emersion/immersion cycles. Copper (Cu2+) appears less toxic to the molluscan mitochondria than Cd2+ (Ivanina et al. 2013; Ivanina and Sokolova 2013) albeit the toxic mechanisms of both trace metals are similar (Valko et al. 2005). This may reflect better handling capacity of Cu by mollusks as reflected in the lower accumulated Cu burdens (compared with those of Cd) in the whole tissues and the mitochondria during metal exposures (Sokolova et al. 2005a; Hawkins and Sokolova 2017). Interestingly, low pH reduces the mitochondrial toxicity of Cd2+ and Cu2+ in oysters as well as clams indicating that mild acidosis may exert cytoprotective effects in polluted habitats (Ivanina and Sokolova 2013). Besides metals, mitochondria of aquatic organisms are susceptible to other environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), antibiotics, and pesticides as discussed in recent excellent reviews (Meyer et al. 2013; Jayasundara 2017). The mechanisms and environmental implications of the mitotoxicity of pollutants have not been extensively investigated in intertidal organisms. Future studies are needed to further elucidate the responses of organisms from highly stressful environments such as the intertidal zone to mitochondrial poisons (including metals, organic pollutants, metal-containing nanoparticles, and their mixtures) alone and in combination with other abiotic stressors. Outlook and future challenges Mitochondria of intertidal animals exhibit high tolerance to common environmental stressors in their habitats including temperature stress, fluctuations in osmolarity and ion concentrations, and intermittent hypoxia. A notable exception includes high sensitivity of mitochondria of intertidal mollusks to inhibition by pH shifts and may represent an adaptive mechanism to support stress-induced metabolic rate depression. Sensitivity of molluscan mitochondria to trace metals such as Cd2+ and Cu2+ likely indicates the lack of prior exposure to these recently introduced anthropogenic stressors and emphasizes that mitochondrial tolerance mechanisms are stressor-specific. Future studies are required to identify specific molecular targets responsible for the exceptional robustness of mitochondria from intertidal organisms to temperature, salinity, and hypoxia stress. Mitochondrial ETS is a promising target for identification of such mechanisms since ETS controls a large proportion (∼80–90%) of the OXPHOS capacity under the optimum as well as the stressful conditions (Dufour et al. 1996; Chamberlin 2004; Kurochkin et al. 2011; Ivanina et al. 2012). Interestingly, convergent evolution of key mitochondrial ETS complexes was implicated in aquatic–terrestrial transitions of in several molluscan lineages (Romero et al. 2016) and in adaptations to chronic hypoxia in mammals (Tian et al. 2017) emphasizing the key role of ETS adjustments in conquering the stressful environments. Therefore, investigation of the molecular diversity of ETS complexes in different environments as well as the epigenetic and post-translational mechanisms that regulate mitochondrial ETS capacity in animals from highly stressful environments are promising avenues for future discoveries. Mitochondrial proteostasis and redox homeostasis are another important contributor to mitochondrial stress tolerance of intertidal organisms (Ivanina et al. 2016; Ivanina and Sokolova 2016) requiring further investigations. To date, most studies of mitochondrial physiology of intertidal organisms have been focused on bioenergetics and oxidative stress. With the rapidly developing molecular tools that can be used in non-model organisms, the field is ripe to move beyond the mitochondrial bioenergetics and ROS and explore the ways in which mitochondrial metabolism, cell signaling, and immunity are coordinated to facilitate survival in stressful environments. Such underexplored yet potentially fruitful areas of future research include the potential roles of mitonuclear interactions in mitochondrial fitness under extreme stress and the role of mitochondrial dynamics (fusion, fission, proliferation, and mitophagy) in environmental stress adaptations. Furthermore, recent genomic studies demonstrate “stressome expansion,” i.e., proliferation of stress-related genes such as those encoding molecular chaperones and antioxidants in stress-tolerant intertidal mollusks such as Pacific oysters (Zhang et al. 2012). It would be intriguing to determine whether similar gene expansion has occurred in mitochondrial stressome of organisms adapted to the intertidal zone and other stressful environments. Comparisons of the mitochondrial physiological and molecular responses to stress in stress-tolerant intertidal species with those of stress-sensitive organisms including well-studied animal models (such as terrestrial mammals and insects) could help identify the physiological weak links responsible for the mitochondrial susceptibility to stress, discover the evolutionarily tested solutions to overcome these weaknesses, and might generate novel hypotheses for the strategies to mitigate mitochondrial stress in other systems (such as domestic animals and humans). Acknowledgments I thank the Society for Integrative and Comparative Biology (SICB), the Company of Biologists, and the National Science Foundation (award IOS-1738378 to Wendy Hood and Karine Salin) for travel support to the annual SICB meeting in San Francisco (2018), and the organizers and attendees of the “Inside the Black Box: The Mitochondrial Basis of Life-History Variation and Animal Performance” symposium for enthusiastic and productive discussions. The useful comments of three anonymous reviewers on an earlier draft are also gratefully acknowledged. Funding The work was in part supported by the Deutsche Forschungsgemeinschaft (DFG) in the framework of the Research Training Group “Baltic TRANSCOAST” (award number GRK 2000) and by the U.S. National Science Foundation, award IOS-1738378. This is Baltic TRANSCOAST Publication No. GRK2000/0012. References Abele D , Heise K , Pörtner HO , Puntarulo S. 2002 . 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Mitochondrial Adaptations to Variable Environments and Their Role in Animals’ Stress Tolerance

Mitochondrial Adaptations to Variable Environments and Their Role in Animals’ Stress Tolerance

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Mitochondrial Adaptations to Variable Environments and Their Role in Animals’ Stress Tolerance

Mitochondrial Adaptations to Variable Environments and Their Role in Animals’ Stress Tolerance

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