Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury

Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury Acute kidney injury (AKI) remains a major problem in critically unwell children and young adults. Ischaemia reperfusion (IR) injury is a major contributor to the development of AKI in a significant proportion of these cases and mitochondria are increasingly recognised as being central to this process through generation of a burst of reactive oxygen species early in reperfusion. Mitochondria have additionally been shown to have key roles in downstream processes including activation of the immune response, immunomodulation, and apoptosis and necrosis. The recognition of the central role of mitochondria in IR injury and an increased understanding of the pathophysiology that undermines these processes has resulted in identification of novel therapeutic targets and potential biomarkers. This review summarises a variety of therapeutic approaches that are currently under exploration and may have potential in ameliorating AKI in children in the future. . . . . . Keywords Acute kidney injury Children Ischaemia reperfusion injury Mitochondria Reactive oxygen species Succinate Acute kidney injury in paediatric nephrology mitochondria-targeted therapies, there is increasing interest in the application of such therapies to the management of AKI Acute kidney injury (AKI) remains a major problem in criti- [5]. cally unwell children and young adults and is recognised as a major risk factor for the development of chronic kidney dis- ease [1, 2]. The reported incidence of AKI varies between Ischaemia reperfusion injury and reactive studies; a consequence in part of different case mix of institu- oxygen species tions and variable definitions of AKI. In a multinational study, 26.9% of patients admitted to paediatric intensive care units Reperfusion injury is the paradoxical, pathological exacerba- were observed to have AKI. Importantly, in these children, tion of tissue injury that occurs on re-oxygenation of an organ AKI was an independent risk factor for morbidity and mortal- that has previously been subjected to a period of ischaemia ity, highlighting the urgent need for the development of effec- [6]. While early research into this process focused on the heart tive therapies to prevent and treat AKI [3, 4]. Ischaemia reper- [7–10], it is now increasingly recognised that the underlying fusion (IR) injury is a major contributor to the development of pathophysiological process is common to a wide range of AKI in a significant proportion of children. Mitochondria are disorders, including AKI, stroke, intestinal ischaemia, multi- increasingly recognised to have a fundamental role in the organ failure, hypovolaemic shock and organ dysfunction af- pathogenesis of IR injury, and with the development of novel ter transplantation [6]. It is well recognised that the dominant injurious effector upon reperfusion is an early burst of reactive oxygen species * Kourosh Saeb-Parsy (ROS). Mitochondria are increasingly recognised as the key ks10014@cam.ac.uk source of these ROS, through the generation of a burst of 1 superoxide upon reperfusion, and these findings have been Department of Surgery and Cambridge NIHR Biomedical Research corroborated across a range of tissue types, including renal Centre, Biomedical Campus, University of Cambridge, Cambridge CB2 2QQ, UK tissue [11, 12]. Whilst thereareanumber of alternative sources of superoxide, including the xanthine oxidase path- MRC Mitochondrial Biology Unit, Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK way and NADPH oxidases that are thought to be important in Pediatr Nephrol renal IR injury [13], activation of these pathways seems to disease severity. The therapeutic strategies can be grouped occur after, and be secondary to, the initial mitochondrial burst into the following areas and are discussed in more detail be- of superoxide formation [11, 14]. low: limiting oxidative stress and mitochondrial ROS genera- tion, reducing tubular cell death through necrosis and apopto- sis, moderating mitochondrial dynamics and mitochondrial Mitochondrial generation of reactive oxygen immunomodulation. species Mitochondria oxidative stress Reactive oxygen species generation by mitochondria has long been known to occur during both physiological and patho- The fundamental role of mitochondrial oxidative stress in a physiological conditions. However, until recently, superoxide wide range of pathologies including IR injury has been exten- production during reperfusion was presumed to be the result sively reported in the literature and has provided a strong of generalised dysregulation of the electron transport chain, rationale for the use of antioxidants as a therapeutic interven- with electrons leaking at multiple non-specific sites when ox- tion. Unfortunately, the clinical translation of non-specific an- ygen was re-introduced to a system in biochemical disarray tioxidants has been almost universally disappointing. This following a period of ischaemia [11]. paradox can be interpreted in one of two ways. Either reactive Contrary to this view, Chouchani et al. recently identified a oxygen species do not have a role in the pathophysiology of specific metabolic pathway in which superoxide was generat- these diseases or the antioxidants are not adequately delivered ed through reverse electron transport at complex I of the elec- to the appropriate region of the cell to prevent oxidative dam- tron transport chain. Moreover, this process was shown to be age. This second argument is supported by the increasing driven by the pool of the citric acid cycle metabolite, succi- recognition of the important physiological roles of ROS with- nate, that accumulates during ischaemia (Fig. 1)[15]. in the cell and the recognition of the integral role of the burst This burst of mitochondrial superoxide leads to the activation of mitochondrial ROS in mediating IR injury. Targeting anti- of a plethora of pathways that cause tissue injury. Direct cellular oxidants to mitochondria, therefore, provides an approach that or mitochondrial damage through lipid peroxidation or protein could both explain this paradox and provide a novel therapeu- carbonylation results in disruption of adenosine triphospate tic strategy in IR injury [5, 21]. (ATP) generation, dysregulation of calcium levels and induction Bioactive molecules and drugs, including antioxidants, of the mitochondrial permeability transition pore (MPTP) with have been targeted to mitochondria in vivo using both lipo- subsequent activation of necrosis and apoptosis. Tissue damage philic cations and mitochondrial targeted peptides (reviewed can also occur indirectly through activation of the innate and in detail elsewhere [21]). Both these approaches lead to a rapid adaptive immune response by damage-associated molecular pat- and significant accumulation of the targeted compound within terns (DAMPs). These DAMPs can be cellular (e.g. high mobil- the mitochondria. This approach increases potency whilst en- ity group box 1 (HMGB1), hyaluronan [16]) or directly mito- abling a lower dose to be administered, minimising off-target chondrial in origin. Mitochondrial ROS, generated by IR injury, effects and toxicity. Triphenylphosphonium (TPP) is a lipo- have been shown to act directly as a DAMP. Furthermore, open- philic cation that is rapidly taken up into mitochondria and ing of the MPTP in response to mitochondrial dysfunction re- concentrated several hundred-fold due to the large mitochon- leases other mitochondrial DAMPs [17, 18]suchasmtDNA, drial membrane potential in vivo. Covalent linkage of bioac- cytochrome c, succinate and N-formyl peptides [19, 20]. These tive molecules or drugs to TPP has been used for a wide range processes provide a putative mechanism for the impact of mito- of compounds [21–24]. The most extensively investigated of chondrial dysfunction on longer-term renal function after an ep- these is MitoQ. The bioactive molecule of MitoQ is isode of AKI. The identification of a unifying, specific pathway ubiqinone. This is rapidly reduced in mitochondria to the also provides a potential explanation for the vast array of inter- chain-breaking antioxidant ubiquinol, which directly scav- ventions and therapies that have previously been shown to ame- enges mitochondrial ROS, inhibiting downstream lipid perox- liorate IR injury [11]. idation and mitochondrial damage. MitoQ has been shown to protect against oxidative injury in a variety of animal models and has been used in phase II human trials [25, 26]. In models Mitochondrial therapeutic strategies in IR of renal IR injury, MitoQ has recently been demonstrated to injury reduce markers of oxidative injury, renal function and tissue injury following IR injury [27–29]. The recent progress in our understanding of the pathophysio- Another approach is through the use of peptide delivery logical mitochondrial mechanisms that underpin IR injury has systems including the Szeto-Schiller (SS) peptides and the led to an array of potential applications of mitochondria as mitochondrial penetrating peptides. The precise mechanism of action of these molecules is not understood, but they have both targets for therapeutic strategies and as biomarkers of Pediatr Nephrol Fig. 1 Mitochondrial generation A Ischaemia of reactive oxygen species (ROS) during ischaemia reperfusion in- Mitochondrial inner membrane jury. Under normoxic conditions, the electron transport chain (ETC) Mitochondrial matrix transfers electrons from NADH ATP and FADH to oxygen via a series 2 Synthase ATP of redox reactions. In this process, H is pumped out of the mito- ADP + P chondria generating a proton mo- tive force. It is this proton motive Succinate Fumarate that drives the production of en- NADH + Inacve NAD ergy, in the form of adenosine tri- + + 4H 2H 4H phosphate (ATP), by ATP syn- H O thase. During ischaemia, without QH oxygen to accept electrons, the ETC rapidly ceases and the elec- Complex I SDH Complex III Complex IV tron donors and carrier pools such (Complex II) as NADH and coenzyme Q 4H (CoQ) become maximally re- duced. Mitochondria briefly B Reperfusion compensate for this by the oxida- tion of fumarate to succinate thereby replenishing the reduced Mitochondrial inner membrane carrier pools but generating a pool of succinate in the process. On Mitochondrial matrix ATP reperfusion, the succinate that ac- Synthase cumulates during ischaemia is ATP rapidly oxidised maintaining a ADP + P reduced CoQ pool and an envi- ronment that favours reverse Fumarate Succinate electron transport (RET) and the ROS generation of reactive oxygen 2H 4H species (superoxide) - H O Q QH QH Q Complex I SDH Complex III Complex IV (Complex II) 4H + + 4H 2H been proposed to protect mitochondria by interacting with difference in mechanisms of mitochondrial ROS generation cardiolipin [30]. SS peptides have also been shown to amelio- is unlikely, given the very early evolutionary origin of mito- rate renal IR injury in rodents and have been studied in other chondria, and it is essential to rule out differences in experi- models of IR pathologies [31]. The lead compound in this mental methodology as a source of conflicting data. group, SS-31, has been investigated in larger animal models Therefore, preventing succinate accumulation by inhibiting and is currently the subject of a human clinical trial investi- succinate dehydrogenase activity remains a potentially impor- gating its efficacy in ameliorating IR injury post-angioplasty tant, but as yet unexplored, area of therapy in renal IR injury. for renal artery stenosis [32]. Furthermore, the demonstrated therapeutic potential in other The recognition of a specific metabolic pathway that drives models of IR injury make it an appealing mechanism that mitochondrial ROS production during IR injury opens up the warrants future investigation (Fig. 2). possibility of a novel therapeutic strategy that acts upstream of ROS generation [15], namely competitive inhibition of succi- Tubular death through apoptosis and necrosis nate dehydrogenase, which has been shown to ameliorate IR injury in a variety of in vivo models [15, 33]. The metabolic Mitochondria are recognised to be integral to the processes of signature of ischaemic succinate accumulation has been dem- necrosis and apoptosis which underlie tubular injury and cell onstrated in a wide range of tissues including human myocar- death following IR injury [12]. In mammalian cells, apoptosis dial [34] and renal tissue [35]. Contrary to these findings, is initiated through two major but interconnected pathways: some authors have questioned the translation of these findings death receptors and mitochondria. The mitochondrial pathway in small animals to human tissues [36]. An inter-species is characterised by an increase in the permeability of the outer Pediatr Nephrol 1. MitoQ Ubiquinone Triphenylphosphonium (TPP) 2. SS pepdes (eg. SS-31) 3. Dimethyl Malonate malonate Fig. 2 Mitochondrial agents targeting reactive oxygen species in of Szeto-Schiller (SS) peptides is less well characterised but it is thought ischaemia reperfusion. A number of approaches have been investigated to interact with cardiolipin. They have demonstrated efficacy in a range of in vivo to target mitochondrial reactive oxygen species (ROS) during models in reducing IR injury. 3. The small molecule competitive inhibitor ischaemia reperfusion (IR) injury. 1. Triphenylphosponium (TPP) is rap- of succinate dehydrogenase, malonate, has been shown to reduce idly taken up into mitochondria and concentrated several hundred-fold. IR injury in a range of in vivo models. Dimethyl malonate can be Bioactive molecules can be covalently linked to TPP thus enabling the administered intravenously and is rapidly hydrolysed to malonate. selective, rapid uptake of these molecules into mitochondria. MitoQ is an Malonate rapidly diffuses across the cellular and mitochondrial example of this approach. The bioactive molecule of MitoQ is ubiqui- membranes where it can then competitively inhibit succinate de- none. This is a chain breaking antioxidant that directly scavenges mtROS hydrogenase and reduce the accumulation of succinate during is- thereby preventing downstream tissue damage. 2. The precise mechanism chaemia and IR injury mitochondrial membrane (MOMP) with the release of pro- These processes are all essential for normal mitochondrial and apoptotic factors such as cytochrome c. The B-cell lymphoma cellular function [41, 42] and have been shown to be impli- 2 (Bcl-2) family proteins are important regulators of MOMP, cated in AKI. both in a positive and negative capacity [37]. The release of Altered mitochondrial dynamics contributes to changes in cytochrome c, and other proteins, from the intermembrane mitochondrial energetics, cellular injury and repair following space triggers the formation of the apoptosome which consists AKI [42]. A variety of mammalian proteins have been identi- of cytochrome c, apaf-1 and caspase-9. This then activates fied as regulators of mitochondrial fission and fusion includ- downstream caspase-activation pathways resulting in apopto- ing the pro-fusion proteins, mitofusin 1 and 2, and OPA1, and sis. However, despite the potential promise of therapies de- the pro-fission protein dynamin-related protein1 (DRP1) [5, signed to inhibit apoptosis in AKI, it has yet to be realised in 43, 44]. The activation of DRP1 results in the translocation of routine clinical practice [38]. A promising approach that is DRP1 to the outer mitochondrial membrane promoting mito- currently in phase II human clinical trials to treat AKI is the chondrial fission and exacerbating AKI. Pharmacological in- use of a small interfering RNA (siRNA) that temporarily in- hibition of DRP1 in a mouse model of AKI reduces mitochon- hibits expression of the stress response gene p53 [39, 40]. drial fission and ameliorates AKI in vivo [45]. Sirtuin 3 Other approaches that target the same pathway include (SIRT3) has also been shown to have a functional role in disrupting steps in the apoptotic pathway using small mole- mitochondrial dynamics, preserving mitochondrial integrity cules, caspase inhibitors and recombinant proteins [12]. by preventing DRP1 translocation. SIRT3 upregulation was shown to be protective in vitro in human proximal tubular epithelial cells damaged by cisplatin. Furthermore, in a murine Mitochondrial biogenesis, mitophagy and dynamics model of AKI, upregulation of SIRT3 resulted in a decrease in −/− mitochondrial fission whilst SIRT3 deficiency in the Sirt3 Mitochondria are highly dynamic organelles existing not as mice exacerbated cisplatin-induced AKI [46]. solitary, isolated entities but as a complex, interconnected net- In the murine kidney, mitophagy has been shown to be work that undergoes continuous biogenesis, fusion, fission highly active [47, 48], with an integral role in moderating and the selective removal by autophagy, termed mitophagy. Pediatr Nephrol tissue injury in the kidney. Ablation of key genes that regulate kidney injury [51]. More recently, sirtuins have also been autophagy, such as autophagy-related protein 7 (ATG7) and shown to have regulatory roles in mitochondria biogenesis, ATG5, has been shown to exacerbate AKI in vivo [48, 49]. and the SIRT1 activator SRT1720 has been shown to augment There is also evidence that there is crosstalk between the cell mitochondrial recovery and tubular function in the rat in vivo death machinery and mitophagy. Deletion of the pro-apoptotic following IR injury [52]. There is also emerging evidence that protein BAK has been shown to be reno-protective in models the β -antagonist formoterol has effects as an activator of of IR injury. This reno-protective effect was associated with a mitochondrial biogenesis and can enhance recovery of mito- decrease in the release of cytochrome c and mitochondrial chondria and kidney function following IR injury [5, 53]. fragmentation [37]. Following AKI, the resolution of kidney injury and return Mitochondrial immunomodulation of function is primarily through restoration of cellular function rather than regeneration and cell proliferation. Therefore, Mitochondria are increasingly being recognised as having moderating mitochondrial biogenesis may provide another critical roles in activating and moderating the immune system therapeutic avenue in AKI [42, 50]. Peroxisome proliferator- though a range of pathways [17, 54, 55]. In adult kidney activated receptor-γ coactivator-1α (PGC-1α) has been iden- transplantation, there is evidence to suggest that prolonged tified as a key regulator of mitochondrial biogenesis and PGC- cold ischaemia impacts on long-term graft survival. Despite 1α knock-out mice have been shown to be more susceptible to significant improvements in short-term outcomes, the Fig. 3 The role of mtDNA in activating the innate immune response. Ischaemic damage- induced loss of membrane poten- tial and mitochondrial swelling Mitochondrion can lead to opening of a non- RO S RO S selective permeability transition RO S Proteins pore (MPTP) in the mitochondrial mtDNA RO S Lipids inner membrane that releases mi- tochondrial molecules, like cyto- RO S mtDNA chrome c,ATP, ROS, N-formyl peptides and mtDNA, into the cytosol. Released mitochondrial components can act as mitochon- drial damage associated molecu- MPTP lar patterns (mtDAMPs). When released, they function as signals Cytochrome c for injury in cells and activate the mtROS Cardiolipins innate immune response. mtDNA mtDAMPs ATP MtDNA, due to its similarity to N-formyl Peptides bacterial DNA, can activate the etc. TLR9 dependent immune re- sponse and in turn stimulate acti- vation of the transcription factor NF-κB and therefore expression of the cytokine IL-6, which is re- leased from the cell and functions as a stimulus for immune cells. In addition, mtDNA is involved in the activation of the NLRP3 Recognition by NLRP3 Inflammasome inflammasome that senses cyto- DNA sensing via STING Activation the TLR9 receptor solic DNA and stimulates the caspase-1-dependent release of NFκB downstream IL-1β and IL-18. Furthermore, Caspase-1 cytokines Type I IFN the ER-linked STING pathway IL-1β can be activated inducing the ex- pression of interferon type 1 and its inflammatory signalling INNATE IMMUNE pathways RESPONSE Pediatr Nephrol prevalence of chronic allograft dysfunction remains largely Summary unchanged [56]. The emerging evidence that mitochondria are not only integral to IR injury but also have fundamental AKI remains a major problem in children and IR injury is either roles in the immune response suggests there may be new av- the primary aetiology or is implicated in a significant proportion enues to improve long-term graft outcomes. Mitochondria, for of cases. Mitochondrial dysfunction or damage are increasingly example, are thought to be involved in regulation of conver- recognised as fundamental to IR injury, generating the burst of sion of M1 inflammatory macrophages to M2 anti- ROS that initiates downstream tissue injury. They also have key inflammatory cells. Both metformin and rotenone have been roles in a variety of downstream processes, including the direct shown to facilitate this switch, possibly mediated through ac- activation of the innate immune response, immunomodulation, tions on complex I by reducing reverse electron transport and and apoptosis and necrosis. Plasma and urinary mtDNA may ROS [17, 57, 58]. Furthermore, the inhibition of ROS gener- have roles as biomarkers of IR injury in the future and there are ation by inhibiting SDH has also been shown to limit pro- a number of therapeutic strategies that are being explored to inflammatory responses and boost anti-inflammatory re- ameliorate mitochondrial dysfunction. We look forward with in- sponses [58, 59]. terest to the translation of these promising strategies to the man- Recently, it has also been suggested that maladaptive agement of AKI in children in the future. repair following AKI may be responsible for the pro- Acknowledgements This work was supported by a grant from the gression of renal disease and development of chronic Medical Research Council. The research was supported by the National kidney disease in affected individuals [60]. Interestingly, Institute for Health Research Blood and Transplant Research Unit (NIHR the cellular changes underlying maladaptive repair, most BTRU) in Organ Donation and Transplantation at the University of notably cellular senescence in tubular epithelial cells Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT). The views expressed are and adoption of a pro-fibrotic phenotype, mimic those those of the author(s) and not necessarily those of the NHS, the NIHR, of kidney ageing [60, 61]. the Department of Health or NHSBT. Compliance with ethical standards Mitochondrial DNA release as a biomarker of kidney injury Conflicts of interest M.P.M. holds patents in the area of mitochondrial therapies and has a financial interest in a company Antipodean Inc. that is commercialising mitochondrial therapies. J.L.M., A.V.G., T.E.B. and The damage to mitochondria associated with IR injury results K.S.P. have no conflicts of interest. in the opening of the MPTP with the consequent release of a number of mitochondrial components into the cytosol. These Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// function as DAMPs, activating an innate immune response creativecommons.org/licenses/by/4.0/), which permits unrestricted use, and driving the systemic inflammatory response associated distribution, and reproduction in any medium, provided you give appro- with IR injury. mtDNA is an example of such a DAMP priate credit to the original author(s) and the source, provide a link to the (Fig. 3). A number of studies have examined the role of cir- Creative Commons license, and indicate if changes were made. culating mtDNA in the blood of patients. The levels of mtDNA have been shown to increase in the circulation fol- lowing trauma [18] and more recently have been shown to References correlate with mortality in intensive care unit patients [62]. It has also been investigated in the clinical context of severe lung 1. 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Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury

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Medicine & Public Health; Pediatrics; Nephrology; Urology
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Abstract

Acute kidney injury (AKI) remains a major problem in critically unwell children and young adults. Ischaemia reperfusion (IR) injury is a major contributor to the development of AKI in a significant proportion of these cases and mitochondria are increasingly recognised as being central to this process through generation of a burst of reactive oxygen species early in reperfusion. Mitochondria have additionally been shown to have key roles in downstream processes including activation of the immune response, immunomodulation, and apoptosis and necrosis. The recognition of the central role of mitochondria in IR injury and an increased understanding of the pathophysiology that undermines these processes has resulted in identification of novel therapeutic targets and potential biomarkers. This review summarises a variety of therapeutic approaches that are currently under exploration and may have potential in ameliorating AKI in children in the future. . . . . . Keywords Acute kidney injury Children Ischaemia reperfusion injury Mitochondria Reactive oxygen species Succinate Acute kidney injury in paediatric nephrology mitochondria-targeted therapies, there is increasing interest in the application of such therapies to the management of AKI Acute kidney injury (AKI) remains a major problem in criti- [5]. cally unwell children and young adults and is recognised as a major risk factor for the development of chronic kidney dis- ease [1, 2]. The reported incidence of AKI varies between Ischaemia reperfusion injury and reactive studies; a consequence in part of different case mix of institu- oxygen species tions and variable definitions of AKI. In a multinational study, 26.9% of patients admitted to paediatric intensive care units Reperfusion injury is the paradoxical, pathological exacerba- were observed to have AKI. Importantly, in these children, tion of tissue injury that occurs on re-oxygenation of an organ AKI was an independent risk factor for morbidity and mortal- that has previously been subjected to a period of ischaemia ity, highlighting the urgent need for the development of effec- [6]. While early research into this process focused on the heart tive therapies to prevent and treat AKI [3, 4]. Ischaemia reper- [7–10], it is now increasingly recognised that the underlying fusion (IR) injury is a major contributor to the development of pathophysiological process is common to a wide range of AKI in a significant proportion of children. Mitochondria are disorders, including AKI, stroke, intestinal ischaemia, multi- increasingly recognised to have a fundamental role in the organ failure, hypovolaemic shock and organ dysfunction af- pathogenesis of IR injury, and with the development of novel ter transplantation [6]. It is well recognised that the dominant injurious effector upon reperfusion is an early burst of reactive oxygen species * Kourosh Saeb-Parsy (ROS). Mitochondria are increasingly recognised as the key ks10014@cam.ac.uk source of these ROS, through the generation of a burst of 1 superoxide upon reperfusion, and these findings have been Department of Surgery and Cambridge NIHR Biomedical Research corroborated across a range of tissue types, including renal Centre, Biomedical Campus, University of Cambridge, Cambridge CB2 2QQ, UK tissue [11, 12]. Whilst thereareanumber of alternative sources of superoxide, including the xanthine oxidase path- MRC Mitochondrial Biology Unit, Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK way and NADPH oxidases that are thought to be important in Pediatr Nephrol renal IR injury [13], activation of these pathways seems to disease severity. The therapeutic strategies can be grouped occur after, and be secondary to, the initial mitochondrial burst into the following areas and are discussed in more detail be- of superoxide formation [11, 14]. low: limiting oxidative stress and mitochondrial ROS genera- tion, reducing tubular cell death through necrosis and apopto- sis, moderating mitochondrial dynamics and mitochondrial Mitochondrial generation of reactive oxygen immunomodulation. species Mitochondria oxidative stress Reactive oxygen species generation by mitochondria has long been known to occur during both physiological and patho- The fundamental role of mitochondrial oxidative stress in a physiological conditions. However, until recently, superoxide wide range of pathologies including IR injury has been exten- production during reperfusion was presumed to be the result sively reported in the literature and has provided a strong of generalised dysregulation of the electron transport chain, rationale for the use of antioxidants as a therapeutic interven- with electrons leaking at multiple non-specific sites when ox- tion. Unfortunately, the clinical translation of non-specific an- ygen was re-introduced to a system in biochemical disarray tioxidants has been almost universally disappointing. This following a period of ischaemia [11]. paradox can be interpreted in one of two ways. Either reactive Contrary to this view, Chouchani et al. recently identified a oxygen species do not have a role in the pathophysiology of specific metabolic pathway in which superoxide was generat- these diseases or the antioxidants are not adequately delivered ed through reverse electron transport at complex I of the elec- to the appropriate region of the cell to prevent oxidative dam- tron transport chain. Moreover, this process was shown to be age. This second argument is supported by the increasing driven by the pool of the citric acid cycle metabolite, succi- recognition of the important physiological roles of ROS with- nate, that accumulates during ischaemia (Fig. 1)[15]. in the cell and the recognition of the integral role of the burst This burst of mitochondrial superoxide leads to the activation of mitochondrial ROS in mediating IR injury. Targeting anti- of a plethora of pathways that cause tissue injury. Direct cellular oxidants to mitochondria, therefore, provides an approach that or mitochondrial damage through lipid peroxidation or protein could both explain this paradox and provide a novel therapeu- carbonylation results in disruption of adenosine triphospate tic strategy in IR injury [5, 21]. (ATP) generation, dysregulation of calcium levels and induction Bioactive molecules and drugs, including antioxidants, of the mitochondrial permeability transition pore (MPTP) with have been targeted to mitochondria in vivo using both lipo- subsequent activation of necrosis and apoptosis. Tissue damage philic cations and mitochondrial targeted peptides (reviewed can also occur indirectly through activation of the innate and in detail elsewhere [21]). Both these approaches lead to a rapid adaptive immune response by damage-associated molecular pat- and significant accumulation of the targeted compound within terns (DAMPs). These DAMPs can be cellular (e.g. high mobil- the mitochondria. This approach increases potency whilst en- ity group box 1 (HMGB1), hyaluronan [16]) or directly mito- abling a lower dose to be administered, minimising off-target chondrial in origin. Mitochondrial ROS, generated by IR injury, effects and toxicity. Triphenylphosphonium (TPP) is a lipo- have been shown to act directly as a DAMP. Furthermore, open- philic cation that is rapidly taken up into mitochondria and ing of the MPTP in response to mitochondrial dysfunction re- concentrated several hundred-fold due to the large mitochon- leases other mitochondrial DAMPs [17, 18]suchasmtDNA, drial membrane potential in vivo. Covalent linkage of bioac- cytochrome c, succinate and N-formyl peptides [19, 20]. These tive molecules or drugs to TPP has been used for a wide range processes provide a putative mechanism for the impact of mito- of compounds [21–24]. The most extensively investigated of chondrial dysfunction on longer-term renal function after an ep- these is MitoQ. The bioactive molecule of MitoQ is isode of AKI. The identification of a unifying, specific pathway ubiqinone. This is rapidly reduced in mitochondria to the also provides a potential explanation for the vast array of inter- chain-breaking antioxidant ubiquinol, which directly scav- ventions and therapies that have previously been shown to ame- enges mitochondrial ROS, inhibiting downstream lipid perox- liorate IR injury [11]. idation and mitochondrial damage. MitoQ has been shown to protect against oxidative injury in a variety of animal models and has been used in phase II human trials [25, 26]. In models Mitochondrial therapeutic strategies in IR of renal IR injury, MitoQ has recently been demonstrated to injury reduce markers of oxidative injury, renal function and tissue injury following IR injury [27–29]. The recent progress in our understanding of the pathophysio- Another approach is through the use of peptide delivery logical mitochondrial mechanisms that underpin IR injury has systems including the Szeto-Schiller (SS) peptides and the led to an array of potential applications of mitochondria as mitochondrial penetrating peptides. The precise mechanism of action of these molecules is not understood, but they have both targets for therapeutic strategies and as biomarkers of Pediatr Nephrol Fig. 1 Mitochondrial generation A Ischaemia of reactive oxygen species (ROS) during ischaemia reperfusion in- Mitochondrial inner membrane jury. Under normoxic conditions, the electron transport chain (ETC) Mitochondrial matrix transfers electrons from NADH ATP and FADH to oxygen via a series 2 Synthase ATP of redox reactions. In this process, H is pumped out of the mito- ADP + P chondria generating a proton mo- tive force. It is this proton motive Succinate Fumarate that drives the production of en- NADH + Inacve NAD ergy, in the form of adenosine tri- + + 4H 2H 4H phosphate (ATP), by ATP syn- H O thase. During ischaemia, without QH oxygen to accept electrons, the ETC rapidly ceases and the elec- Complex I SDH Complex III Complex IV tron donors and carrier pools such (Complex II) as NADH and coenzyme Q 4H (CoQ) become maximally re- duced. Mitochondria briefly B Reperfusion compensate for this by the oxida- tion of fumarate to succinate thereby replenishing the reduced Mitochondrial inner membrane carrier pools but generating a pool of succinate in the process. On Mitochondrial matrix ATP reperfusion, the succinate that ac- Synthase cumulates during ischaemia is ATP rapidly oxidised maintaining a ADP + P reduced CoQ pool and an envi- ronment that favours reverse Fumarate Succinate electron transport (RET) and the ROS generation of reactive oxygen 2H 4H species (superoxide) - H O Q QH QH Q Complex I SDH Complex III Complex IV (Complex II) 4H + + 4H 2H been proposed to protect mitochondria by interacting with difference in mechanisms of mitochondrial ROS generation cardiolipin [30]. SS peptides have also been shown to amelio- is unlikely, given the very early evolutionary origin of mito- rate renal IR injury in rodents and have been studied in other chondria, and it is essential to rule out differences in experi- models of IR pathologies [31]. The lead compound in this mental methodology as a source of conflicting data. group, SS-31, has been investigated in larger animal models Therefore, preventing succinate accumulation by inhibiting and is currently the subject of a human clinical trial investi- succinate dehydrogenase activity remains a potentially impor- gating its efficacy in ameliorating IR injury post-angioplasty tant, but as yet unexplored, area of therapy in renal IR injury. for renal artery stenosis [32]. Furthermore, the demonstrated therapeutic potential in other The recognition of a specific metabolic pathway that drives models of IR injury make it an appealing mechanism that mitochondrial ROS production during IR injury opens up the warrants future investigation (Fig. 2). possibility of a novel therapeutic strategy that acts upstream of ROS generation [15], namely competitive inhibition of succi- Tubular death through apoptosis and necrosis nate dehydrogenase, which has been shown to ameliorate IR injury in a variety of in vivo models [15, 33]. The metabolic Mitochondria are recognised to be integral to the processes of signature of ischaemic succinate accumulation has been dem- necrosis and apoptosis which underlie tubular injury and cell onstrated in a wide range of tissues including human myocar- death following IR injury [12]. In mammalian cells, apoptosis dial [34] and renal tissue [35]. Contrary to these findings, is initiated through two major but interconnected pathways: some authors have questioned the translation of these findings death receptors and mitochondria. The mitochondrial pathway in small animals to human tissues [36]. An inter-species is characterised by an increase in the permeability of the outer Pediatr Nephrol 1. MitoQ Ubiquinone Triphenylphosphonium (TPP) 2. SS pepdes (eg. SS-31) 3. Dimethyl Malonate malonate Fig. 2 Mitochondrial agents targeting reactive oxygen species in of Szeto-Schiller (SS) peptides is less well characterised but it is thought ischaemia reperfusion. A number of approaches have been investigated to interact with cardiolipin. They have demonstrated efficacy in a range of in vivo to target mitochondrial reactive oxygen species (ROS) during models in reducing IR injury. 3. The small molecule competitive inhibitor ischaemia reperfusion (IR) injury. 1. Triphenylphosponium (TPP) is rap- of succinate dehydrogenase, malonate, has been shown to reduce idly taken up into mitochondria and concentrated several hundred-fold. IR injury in a range of in vivo models. Dimethyl malonate can be Bioactive molecules can be covalently linked to TPP thus enabling the administered intravenously and is rapidly hydrolysed to malonate. selective, rapid uptake of these molecules into mitochondria. MitoQ is an Malonate rapidly diffuses across the cellular and mitochondrial example of this approach. The bioactive molecule of MitoQ is ubiqui- membranes where it can then competitively inhibit succinate de- none. This is a chain breaking antioxidant that directly scavenges mtROS hydrogenase and reduce the accumulation of succinate during is- thereby preventing downstream tissue damage. 2. The precise mechanism chaemia and IR injury mitochondrial membrane (MOMP) with the release of pro- These processes are all essential for normal mitochondrial and apoptotic factors such as cytochrome c. The B-cell lymphoma cellular function [41, 42] and have been shown to be impli- 2 (Bcl-2) family proteins are important regulators of MOMP, cated in AKI. both in a positive and negative capacity [37]. The release of Altered mitochondrial dynamics contributes to changes in cytochrome c, and other proteins, from the intermembrane mitochondrial energetics, cellular injury and repair following space triggers the formation of the apoptosome which consists AKI [42]. A variety of mammalian proteins have been identi- of cytochrome c, apaf-1 and caspase-9. This then activates fied as regulators of mitochondrial fission and fusion includ- downstream caspase-activation pathways resulting in apopto- ing the pro-fusion proteins, mitofusin 1 and 2, and OPA1, and sis. However, despite the potential promise of therapies de- the pro-fission protein dynamin-related protein1 (DRP1) [5, signed to inhibit apoptosis in AKI, it has yet to be realised in 43, 44]. The activation of DRP1 results in the translocation of routine clinical practice [38]. A promising approach that is DRP1 to the outer mitochondrial membrane promoting mito- currently in phase II human clinical trials to treat AKI is the chondrial fission and exacerbating AKI. Pharmacological in- use of a small interfering RNA (siRNA) that temporarily in- hibition of DRP1 in a mouse model of AKI reduces mitochon- hibits expression of the stress response gene p53 [39, 40]. drial fission and ameliorates AKI in vivo [45]. Sirtuin 3 Other approaches that target the same pathway include (SIRT3) has also been shown to have a functional role in disrupting steps in the apoptotic pathway using small mole- mitochondrial dynamics, preserving mitochondrial integrity cules, caspase inhibitors and recombinant proteins [12]. by preventing DRP1 translocation. SIRT3 upregulation was shown to be protective in vitro in human proximal tubular epithelial cells damaged by cisplatin. Furthermore, in a murine Mitochondrial biogenesis, mitophagy and dynamics model of AKI, upregulation of SIRT3 resulted in a decrease in −/− mitochondrial fission whilst SIRT3 deficiency in the Sirt3 Mitochondria are highly dynamic organelles existing not as mice exacerbated cisplatin-induced AKI [46]. solitary, isolated entities but as a complex, interconnected net- In the murine kidney, mitophagy has been shown to be work that undergoes continuous biogenesis, fusion, fission highly active [47, 48], with an integral role in moderating and the selective removal by autophagy, termed mitophagy. Pediatr Nephrol tissue injury in the kidney. Ablation of key genes that regulate kidney injury [51]. More recently, sirtuins have also been autophagy, such as autophagy-related protein 7 (ATG7) and shown to have regulatory roles in mitochondria biogenesis, ATG5, has been shown to exacerbate AKI in vivo [48, 49]. and the SIRT1 activator SRT1720 has been shown to augment There is also evidence that there is crosstalk between the cell mitochondrial recovery and tubular function in the rat in vivo death machinery and mitophagy. Deletion of the pro-apoptotic following IR injury [52]. There is also emerging evidence that protein BAK has been shown to be reno-protective in models the β -antagonist formoterol has effects as an activator of of IR injury. This reno-protective effect was associated with a mitochondrial biogenesis and can enhance recovery of mito- decrease in the release of cytochrome c and mitochondrial chondria and kidney function following IR injury [5, 53]. fragmentation [37]. Following AKI, the resolution of kidney injury and return Mitochondrial immunomodulation of function is primarily through restoration of cellular function rather than regeneration and cell proliferation. Therefore, Mitochondria are increasingly being recognised as having moderating mitochondrial biogenesis may provide another critical roles in activating and moderating the immune system therapeutic avenue in AKI [42, 50]. Peroxisome proliferator- though a range of pathways [17, 54, 55]. In adult kidney activated receptor-γ coactivator-1α (PGC-1α) has been iden- transplantation, there is evidence to suggest that prolonged tified as a key regulator of mitochondrial biogenesis and PGC- cold ischaemia impacts on long-term graft survival. Despite 1α knock-out mice have been shown to be more susceptible to significant improvements in short-term outcomes, the Fig. 3 The role of mtDNA in activating the innate immune response. Ischaemic damage- induced loss of membrane poten- tial and mitochondrial swelling Mitochondrion can lead to opening of a non- RO S RO S selective permeability transition RO S Proteins pore (MPTP) in the mitochondrial mtDNA RO S Lipids inner membrane that releases mi- tochondrial molecules, like cyto- RO S mtDNA chrome c,ATP, ROS, N-formyl peptides and mtDNA, into the cytosol. Released mitochondrial components can act as mitochon- drial damage associated molecu- MPTP lar patterns (mtDAMPs). When released, they function as signals Cytochrome c for injury in cells and activate the mtROS Cardiolipins innate immune response. mtDNA mtDAMPs ATP MtDNA, due to its similarity to N-formyl Peptides bacterial DNA, can activate the etc. TLR9 dependent immune re- sponse and in turn stimulate acti- vation of the transcription factor NF-κB and therefore expression of the cytokine IL-6, which is re- leased from the cell and functions as a stimulus for immune cells. In addition, mtDNA is involved in the activation of the NLRP3 Recognition by NLRP3 Inflammasome inflammasome that senses cyto- DNA sensing via STING Activation the TLR9 receptor solic DNA and stimulates the caspase-1-dependent release of NFκB downstream IL-1β and IL-18. Furthermore, Caspase-1 cytokines Type I IFN the ER-linked STING pathway IL-1β can be activated inducing the ex- pression of interferon type 1 and its inflammatory signalling INNATE IMMUNE pathways RESPONSE Pediatr Nephrol prevalence of chronic allograft dysfunction remains largely Summary unchanged [56]. The emerging evidence that mitochondria are not only integral to IR injury but also have fundamental AKI remains a major problem in children and IR injury is either roles in the immune response suggests there may be new av- the primary aetiology or is implicated in a significant proportion enues to improve long-term graft outcomes. Mitochondria, for of cases. Mitochondrial dysfunction or damage are increasingly example, are thought to be involved in regulation of conver- recognised as fundamental to IR injury, generating the burst of sion of M1 inflammatory macrophages to M2 anti- ROS that initiates downstream tissue injury. They also have key inflammatory cells. Both metformin and rotenone have been roles in a variety of downstream processes, including the direct shown to facilitate this switch, possibly mediated through ac- activation of the innate immune response, immunomodulation, tions on complex I by reducing reverse electron transport and and apoptosis and necrosis. Plasma and urinary mtDNA may ROS [17, 57, 58]. Furthermore, the inhibition of ROS gener- have roles as biomarkers of IR injury in the future and there are ation by inhibiting SDH has also been shown to limit pro- a number of therapeutic strategies that are being explored to inflammatory responses and boost anti-inflammatory re- ameliorate mitochondrial dysfunction. We look forward with in- sponses [58, 59]. terest to the translation of these promising strategies to the man- Recently, it has also been suggested that maladaptive agement of AKI in children in the future. repair following AKI may be responsible for the pro- Acknowledgements This work was supported by a grant from the gression of renal disease and development of chronic Medical Research Council. The research was supported by the National kidney disease in affected individuals [60]. Interestingly, Institute for Health Research Blood and Transplant Research Unit (NIHR the cellular changes underlying maladaptive repair, most BTRU) in Organ Donation and Transplantation at the University of notably cellular senescence in tubular epithelial cells Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT). The views expressed are and adoption of a pro-fibrotic phenotype, mimic those those of the author(s) and not necessarily those of the NHS, the NIHR, of kidney ageing [60, 61]. the Department of Health or NHSBT. Compliance with ethical standards Mitochondrial DNA release as a biomarker of kidney injury Conflicts of interest M.P.M. holds patents in the area of mitochondrial therapies and has a financial interest in a company Antipodean Inc. that is commercialising mitochondrial therapies. J.L.M., A.V.G., T.E.B. and The damage to mitochondria associated with IR injury results K.S.P. have no conflicts of interest. in the opening of the MPTP with the consequent release of a number of mitochondrial components into the cytosol. These Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// function as DAMPs, activating an innate immune response creativecommons.org/licenses/by/4.0/), which permits unrestricted use, and driving the systemic inflammatory response associated distribution, and reproduction in any medium, provided you give appro- with IR injury. mtDNA is an example of such a DAMP priate credit to the original author(s) and the source, provide a link to the (Fig. 3). A number of studies have examined the role of cir- Creative Commons license, and indicate if changes were made. culating mtDNA in the blood of patients. The levels of mtDNA have been shown to increase in the circulation fol- lowing trauma [18] and more recently have been shown to References correlate with mortality in intensive care unit patients [62]. It has also been investigated in the clinical context of severe lung 1. 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Journal

Pediatric NephrologySpringer Journals

Published: Jun 2, 2018

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