TY - JOUR
AU - Camougrand, Nadine
AB - Abstract Mitochondria are essential for oxidative energy production in aerobic eukaryotic cells, where they are also required for multiple biosynthetic pathways to take place. Mitochondria also monitor and evaluate complex information from the environment and intracellular milieu, including the presence or absence of growth factors, oxygen, reactive oxygen species, and DNA damage. It follows that disturbances of the integrity of mitochondrial function lead to the disruption of cell function, expressed as disease, aging, or cell death. It has been assumed that the degradation of damaged mitochondria by an autophagy-related pathway specific to mitochondria (mitophagy), recently found to be strictly regulated, is a fundamental process essential for cell homeostasis. Until now, the main role of mitophagy has been tentatively defined as a ‘house-cleaning’ pathway that allows to eliminate altered mitochondria, but mitophagy may also play a role in the adaptation of the number and quality of mitochondria to new environmental conditions. In yeast, recent data defined two categories of mitophagy actors: ones constitutively required for mitophagy and those with mitophagy-regulatory functions. Situations were also uncovered in normal physiology in which cells utilize mitophagy to eliminate damaged, dysfunctional, and superfluous mitochondria to adjust to changing physiological demands. autophagy, mitochondria, mitophagy, vacuole, yeast Introduction Autophagy is a major pathway involving the lysosomal/vacuolar delivery of long-lived proteins and organelles, where degradation and recycling of materials occurs. Autophagy plays a crucial role in the differentiation and cellular response to stress and is conserved in eukaryotic cells from yeast to mammals (Huang & Klionsky, 2002; Reggiori & Klionsky, 2005). The main form of autophagy, macroautophagy, involves the nonselective sequestration of large portions of the cytoplasm into double-membrane structures termed autophagosomes, and their delivery to the vacuole/lysosome for degradation. Another process, microautophagy, involves the direct sequestration of parts of the cytoplasm by vacuole/lysosomes. The two processes coexist in yeast cells, but their utility may depend on different factors including the metabolic state (Kiššová, 2007). Both macroautophagy and microautophagy are essentially nonselective, in that autophagosomes and vacuole invaginations do not appear to discriminate the sequestered material. However, selective forms of autophagy have been observed (Nair & Klionsky, 2005), whereby the target is specific, including peroxisomes (Sakai, 1998; Kiel, 2003), chromatin (Pan, 2000; Roberts, 2003), endoplasmic reticulum (Hamasaki, 2005), ribosomes (Kraft, 2008), and mitochondria (Lemasters, 1998; Xue, 1999, 2001; Kiššová, 2004, 2007; Kim, 2007; Tal, 2007; Kanki & Klionsky, 2008; Deffieu, 2009; Kanki, 2009a, b; Okamoto, 2009) (Table 1). 1 Basic autophagic nomenclature used in the review Autophagy  Catabolic process involving the degradation of a cell's own components through the lysosomal/vacuolar machinery  Nonselective autophagy  Random cytosolic material including organelles and long-lived proteins is delivered into vacuoles for degradation  Selective autophagy  The target for vacuolar degradation in this case is specifically selected; it can be one type of organelle (peroxisome, mitochondria, endoplasmic reticulum, ribosomes), or long-lived protein  Macroautophagy  Sequestration of a portion of cytosol, organelles, or long-lived proteins in a double-membrane vesicle, called an autophagosome, followed by the fusion of the outer membrane of the autophagosomes in the cytoplasm with the vacuole, where their contents are degraded via acidic hydrolases; can be selective or nonselective  Microautophagy  Occurs when the vacuole directly engulfs cytoplasmic material by invagination, protrusion, and/or septation of the vacuolar limiting membrane; can be selective or nonselective  Mitophagy  Selective vacuolar degradation of mitochondria by an autophagy-related process, which can be separated into macromitophagy and micromitophagy  Macromitophagy  Selective degradation of mitochondria by macroautophagy  Micromitophagy  Selective degradation of mitochondria by microautophagy  Autophagy  Catabolic process involving the degradation of a cell's own components through the lysosomal/vacuolar machinery  Nonselective autophagy  Random cytosolic material including organelles and long-lived proteins is delivered into vacuoles for degradation  Selective autophagy  The target for vacuolar degradation in this case is specifically selected; it can be one type of organelle (peroxisome, mitochondria, endoplasmic reticulum, ribosomes), or long-lived protein  Macroautophagy  Sequestration of a portion of cytosol, organelles, or long-lived proteins in a double-membrane vesicle, called an autophagosome, followed by the fusion of the outer membrane of the autophagosomes in the cytoplasm with the vacuole, where their contents are degraded via acidic hydrolases; can be selective or nonselective  Microautophagy  Occurs when the vacuole directly engulfs cytoplasmic material by invagination, protrusion, and/or septation of the vacuolar limiting membrane; can be selective or nonselective  Mitophagy  Selective vacuolar degradation of mitochondria by an autophagy-related process, which can be separated into macromitophagy and micromitophagy  Macromitophagy  Selective degradation of mitochondria by macroautophagy  Micromitophagy  Selective degradation of mitochondria by microautophagy  View Large 1 Basic autophagic nomenclature used in the review Autophagy  Catabolic process involving the degradation of a cell's own components through the lysosomal/vacuolar machinery  Nonselective autophagy  Random cytosolic material including organelles and long-lived proteins is delivered into vacuoles for degradation  Selective autophagy  The target for vacuolar degradation in this case is specifically selected; it can be one type of organelle (peroxisome, mitochondria, endoplasmic reticulum, ribosomes), or long-lived protein  Macroautophagy  Sequestration of a portion of cytosol, organelles, or long-lived proteins in a double-membrane vesicle, called an autophagosome, followed by the fusion of the outer membrane of the autophagosomes in the cytoplasm with the vacuole, where their contents are degraded via acidic hydrolases; can be selective or nonselective  Microautophagy  Occurs when the vacuole directly engulfs cytoplasmic material by invagination, protrusion, and/or septation of the vacuolar limiting membrane; can be selective or nonselective  Mitophagy  Selective vacuolar degradation of mitochondria by an autophagy-related process, which can be separated into macromitophagy and micromitophagy  Macromitophagy  Selective degradation of mitochondria by macroautophagy  Micromitophagy  Selective degradation of mitochondria by microautophagy  Autophagy  Catabolic process involving the degradation of a cell's own components through the lysosomal/vacuolar machinery  Nonselective autophagy  Random cytosolic material including organelles and long-lived proteins is delivered into vacuoles for degradation  Selective autophagy  The target for vacuolar degradation in this case is specifically selected; it can be one type of organelle (peroxisome, mitochondria, endoplasmic reticulum, ribosomes), or long-lived protein  Macroautophagy  Sequestration of a portion of cytosol, organelles, or long-lived proteins in a double-membrane vesicle, called an autophagosome, followed by the fusion of the outer membrane of the autophagosomes in the cytoplasm with the vacuole, where their contents are degraded via acidic hydrolases; can be selective or nonselective  Microautophagy  Occurs when the vacuole directly engulfs cytoplasmic material by invagination, protrusion, and/or septation of the vacuolar limiting membrane; can be selective or nonselective  Mitophagy  Selective vacuolar degradation of mitochondria by an autophagy-related process, which can be separated into macromitophagy and micromitophagy  Macromitophagy  Selective degradation of mitochondria by macroautophagy  Micromitophagy  Selective degradation of mitochondria by microautophagy  View Large Although nonselective autophagy plays an essential role in survival by nitrogen starvation in providing amino acids to the cell, selective autophagy is more likely to play a role in the maintenance of cellular structures, occurring under normal conditions as a ‘housecleaning’ process, and under stress conditions by eliminating altered organelles and macromolecular structures (Tolkovsky, 2002; Kundu & Thompson, 2005; Lemasters, 2005; Tolkovsky, 2009). Selective autophagy where the target is the mitochondria may be particularly relevant to stress conditions. The mitochondrial respiratory chain is both the main site and the target of reactive oxygen species (ROS) production. Consequently, the maintenance of a pool of healthy mitochondria is a crucial challenge for the cells. The progressive accumulation of altered mitochondria caused by the loss of efficiency of the maintenance process (degradation/de novo biogenesis) is often considered a major cause of cellular aging (Xue, 1999; Jazwinski, 2005; Sanz, 2006; Terman, 2006; Yu & Chung, 2006). A brief history of mitophagy The process of selective removal of mitochondria by autophagy was termed mitophagy by Lemasters in 2005, following decades of research. The first report illustrating the possible presence of mitochondria within lysosomes and single- or double-membrane-bounded vesicles (later called autophagosomes) in mammalian cells came from the study of cellular differentiation in the kidneys of newborn mice by Clark (1957). A few years later, Ashford & Porter (1962) observed that the incidence of lysosomes in rat hepatocytes following their exposure to glucagon was higher than normal, and their typical distribution in cells was altered. The peculiar feature of these glucagon-treated cells was that mitochondria were the most common objects identified in encapsulation and lysis. In addition to cytoplasmic components, small vesicles, and ribonucleoprotein particles, almost every lysosome contained mitochondria in various stages of breakdown or hydrolysis. Because the mitochondria, with the exception of those in sequestration organelles, did not appear to be changed, it was difficult to judge whether mitochondria experienced these changes before or only after their sequestration. Beaulaton & Lockshin (1977), studying the ultrastructural changes in intersegmental muscles that occur during programmed cell death in the metamorphosing muscles of the silk moth, suggested that mitochondria could be selectively removed during insect metamorphosis. They remarked that while other organelles looked completely normal, mitochondria developed some functional and morphological alterations, which could activate autophagy, resulting in the almost exclusive engulfment of mitochondria by autophagosomes. Observations of Decker & Wildenthal (1980) suggested that subcellular damage caused by hypoxia and especially recovery from hypoxia can induce important lysosomal responses in the rabbit heart, including ‘controlled’ autophagy of damaged organelles, especially mitochondria, or fusion of autophagic vacuoles with adjacent degenerating mitochondria, depending on the length of the hypoxic episode and reoxygenation. A quantitative ultrastructural study of normal rat erythroblasts and reticulocytes revealed that they completely eliminate their mitochondria (along with the reduction in the content of other organelles such as the endoplasmic reticulum, Golgi apparatus, and ribosomes) during maturation, and suggested that mitochondria are recycled through an autophagy-related process, specifically by their uptake into autophagosomes in late erythroblasts and in reticulocytes (Heynen & Verwilghen, 1982). The regulated clearance of mitochondria remained a well-recognized, but poorly understood aspect of cellular homeostasis for a long time. Recently, it was found that Bcl-2-related protein NIX is required for programmed mitochondrial clearance during reticulocyte maturation (Schweers, 2007; Sandoval, 2008). Years of detailed studies on the fate of mitochondria in rat hepatocytes after serum deprivation provided Lemasters (1998) with the opportunity to demonstrate that the opening of the mitochondrial permeability transition pore (mPTP) and the loss of mitochondrial membrane potential (ΔΨm) trigger the induction of autophagy. Subsequent studies revealed that autophagy could selectively remove mitochondria (Elmore, 2001). Because the mPTP opening can cause the release of toxic proteins, the authors suggested that autophagy of mitochondria is a protective device used by cells to eliminate harmful/damaged organelles. Lemasters also introduced a model that initiated research on the connection between autophagy and apoptosis, whereby autophagy could serve as a cytoprotective mechanism. For example, in order to preserve the efficiency of the cell, autophagy can target damaged organelles, but if the damage is too extensive, the cell may undergo apoptosis. It has been shown that when cells were induced to undergo apoptosis, but then were prevented from carrying out apoptosis by the concomitant inhibition of caspases and subsequently returned to their normal growth environment, there followed a period during which the entire cohort of mitochondria were selectively eliminated from the cells (Xue, 1999, 2001). Interestingly, it was proposed that mitochondria are responsible for initiating their own death. Analysis of autophagy in the yeast system dates back 18 years, when it was demonstrated that the autophagy morphology in yeast was similar to that documented in mammals (Takeshige, 1992). This result was fundamental to enable further studies in this genetic model organism. This same study reported the presence of mitochondria in autophagosomes sequestered with other cytoplasmic constituents following autophagy induction by nitrogen starvation in the presence of a fermentative carbon source of glucose, suggesting a nonselective manner of mitochondrial removal in yeast under these conditions (Takeshige, 1992). Vacuole-dependent and selective uptake of mitochondria has been found in yeast Δyme1 mutant cells growing on an ethanol/glycerol medium (Campbell & Thorsness, 1998). Yme1 protein is mitochondrial AAA ATPase that controls the escape of mtDNA from the mitochondria to the nucleus, in the budding yeast Saccharomyces cerevisiae. In its absence, an increased rate of escape of mtDNA in cells was accompanied by the appearance of ‘pinched’ and fragmented mitochondria adjacent to invaginations at the surface of the vacuole. Thus, YME1 was the first identified gene where complete absence triggered a specific mitochondrial turnover. Whether autophagy is involved, and what kind of autophagy, was unclear. A key point in our understanding of the selective mitochondrial degradation by autophagy (mitophagy) only occurred following analyses of yeast cells shifted to nitrogen starvation or in the stationary phase under respiratory conditions (Kiššová, 2004, 2006a, 2007; Tal, 2007; Zhang, 2007; Kanki & Klionsky, 2008; Deffieu, 2009; Journo, 2009; Kanki, 2009a, b; Okamoto, 2009). In the yeasts, the mitochondrial function, morphology, and the extent of autophagic activity depend on the growth conditions. On glucose, yeast obtains energy by fermentation, and the Crabtree effect prevents the differentiation of fully functional mitochondria. However, on a respiratory carbon source (lactate or glycerol/ethanol), mitochondrial respiration is essential for growth and viability, mitochondrial biogenesis is vigorous, and, as a result, cells contain a high number of optimally differentiated mitochondria. Thus, elimination of mitochondria during growth in glucose and in a respiratory carbon source may have to involve various/distinct mechanisms and may also have diverse consequences on the cells. The results obtained have allowed the definition of two categories of actors in mitophagy: ones constitutively required for mitophagy and those with mitophagy regulatory functions. Mitophagy and ATG genes The first autophagic mutant, designated as Δatg1, and defective in the accumulation of autophagic bodies in the vacuoles of yeast cells grown in various nutrient-deficient media was isolated by selection using a light microscope by Tsukada & Ohsumi (1993). Seventeen years of focused effort to conduct different genetic screens for autophagy have allowed the identification of 33 autophagy-related genes (ATG) to date. The ATG gene products are needed for the Cvt pathway, nonspecific macro- and microautophagy, and also for selective autophagic pathways. About half of the Atg proteins form the core machinery essential for the biogenesis of autophagosomes. Other Atg proteins adapt this core machinery to the needs of autophagic subtypes. In S. cerevisiae, the core Atg proteins colocalize at the site of autophagosome biogenesis [autophagosome assembly site (PAS)] and form functional complexes, which assemble hierarchically. The serine/threonine protein kinase, Atg1p, and its regulatory factor Atg13p, form a basic scaffold for PAS assembly during starvation. In rich media, Atg13p is phosphorylated depending on the rapamycin-sensitive TOR kinase. Upon induction of autophagy, Atg13p is dephosphorylated, and together with other proteins, interacts with Atg1p. This stimulates Atg1 kinase activity and modulates the autophagic response. The formation of autophagosomes is initiated by class III phosphoinositide 3-kinase and Atg6p. The combination of several other Atg proteins and two conjugation events is essential for the process by which the double membrane enwraps and sequesters cytosol during autophagy. The first event is the covalent attachment of Atg12p to Atg5p in a ubiquitin-like conjugation process in association with Atg7 and Atg16 proteins. This multiconjugate complex is directly required for vesicle formation and is also a prerequisite for membrane association of Atg8p in a second conjugation reaction. Atg8p mediates membrane tethering and is essential for the formation of normal-sized vesicles. The source of lipids for membrane expansion at the PAS is largely unknown. There are hints of an involvement of the mitochondria, the trans-Golgi network, and the endocytic system cluster (Farre, 2009). At the time the existence of the process of mitophagy was discovered, the possible involvement of Atg proteins in the process was tested, revealing the requirement for Atg1,5–9,12–13 proteins (Kiššová, 2004, 2007; Tal, 2007; Zhang, 2007). However, the absence of these proteins disabled all forms of autophagy. Some Atg proteins are required only for selective autophagy, as in the case of Atg11p, an essential adaptor or scaffold protein for pexophagy (Kim, 2001). It was found that the Atg11 protein was also indispensable for mitophagy induced during nitrogen starvation or in the stationary phase under respiratory conditions (Kanki & Klionsky, 2008; Okamoto, 2009). The role of this protein was to recruit the degradation-sentenced organelle to the PAS. Very recently, by performing screens on a yeast knockout library for mitophagy-deficient mutants, two different research groups identified the same protein, named Atg32p (Kanki, 2009a; Okamoto, 2009). This mitochondrial protein was essential for mitophagy, but was not required, in contrast to Atg11p, for other types of selective autophagy or for nonspecific macroautophagy. Furthermore, data suggested that the Atg32 protein interacts with Atg11p and Atg8p, and may act as a mitochondrial receptor specific to mitophagy. Another mitochondrial protein, Atg33, was observed to detect or present aged mitochondria for degradation at the stationary phase. In addition, some Atg proteins specific for bulk autophagy and the Cvt pathway were not essential for mitophagy. These results suggested that mitophagy is a bona fide autophagy-related process that is mechanistically distinct from nonspecific autophagy and the Cvt pathway. Interestingly, there is some discrepancy in the results from these two independent screens possibly because of the different conditions under which the screen was performed (the stationary phase for Okamoto's study vs. a shift to nitrogen starvation media with glucose for Kanki's study), and this can suggest a variation in the mechanism of mitophagy induced under different conditions. Recent progress in the understanding of mitophagy in yeast indicated that the initial step of the molecular mechanism for the delivery of mitochondria into vacuoles is the interaction of Atg32 and Atg11 proteins. Nevertheless, how this interaction is regulated, what induces it, and the identity of the signal transduction proteins/molecules relating to mitochondrial function(s) involved in this pathway remain unclear. Two potential candidates to be evaluated are mitochondrial proteins Uth1p and Aup1p, both known to be required for the regulation of mitophagy induction under certain conditions. Regulatory mitophagy players Uth1 The first evidence that mitophagy in yeast is genetically controlled has been obtained by work on the UTH1 gene (Camougrand, 2004; Kiššová, 2004, 2007). The UTH1 gene was identified in two independent genetic screens: the first one was based on the isolation of strains exhibiting an increased life span during starvation stress (Kennedy, 1995), and later, it was also identified in the screen designed to find yeast genes, in the absence of which cells showed altered sensitivities to oxidative damage (Bandara, 1998). The protein encoded by this gene possessed a double cellular localization (outer mitochondrial membrane and cell wall), and its absence promotes pleiotropic effects at different cellular levels such as aging, oxidative stress response, and mitochondrial biogenesis. Moreover, a strain in which the UTH1 gene was deleted exhibited resistance to the heterologous expression of the mammalian proapoptotic protein Bax (Camougrand, 2003). Interestingly, the absence of Uth1p also conferred resistance to rapamycin and nitrogen starvation under both respiratory and fermentative conditions (Kiššová, 2004). Under respiratory conditions, nitrogen starvation as well as rapamycin treatment induced early autophagic removal and degradation of mitochondria. Using different approaches including fluorescent and electron microscopy studies in a wild-type strain and a strain with a deleted UTH1 locus, the existence of two distinct processes was revealed for mitochondrial autophagy. The first, a mitochondria-specific process, did not appear in the absence of Uth1p, and was characterized by the early occurrence of direct contacts between mitochondria and vacuoles, possible fusion between these two organelles, and the later appearance of vacuolar vesicles containing almost exclusively mitochondria with only residual cytosol. The second process was present in both wild-type and mutant strains and involved a nonexclusive engulfment of the mitochondria, with a significant proportion of surrounding cytosol at the vacuolar surface, as readily expected from nonselective microautophagy. As a consequence of the deficiency in the first process, the overall mitochondria autophagy appeared to be poorly efficient in the uth1 mutant, but it was not abolished completely (Kiššová, 2007; Camougrand, 2008). Based on these observations, it is evident that Uth1p has a function in mitophagy distinct from that observed for Atg32p, where its absence prevented mitophagy entirely. The autophagic machinery is fully functional in the absence of Uth1p (Kiššová, 2004). It is not clear whether the lack of the Uth1 protein itself is the signal for mitophagy or whether other proteins participate in the essential signal response chain by acquiring abnormal or novel functions in the absence of the primary proteins. Aup1 Abeliovich and colleagues have identified and characterized Aup1 protein, a yeast mitochondrial protein phosphatase homolog that functionally interacts with the autophagy-dedicated protein kinase Atg1p (Tal, 2007). The absence of Aup1p does not cause a defect in starvation-induced nonspecific macroautophagy; however, Aup1p is required for efficient mitophagy in prolonged stationary-phase incubation in a medium containing lactate as a carbon source. The reduction in mitophagy in the Δaup1 mutant cells is correlated with reduced viability and rapamycin hypersensitivity, suggesting a prosurvival role for Aup1-directed mitophagy. Aup1p is also involved in the phosphorylation of Pda1p, the α-subunit of the pyruvate dehydrogenase complex (Gey, 2008), which is responsible for the formation of acetyl-CoA, and is essential for the tricarboxylic acid (TCA) cycle and respiration. The mitochondrial TCA cycle participates in nitrogen assimilation through the amination of oxaloacetate and α-ketoglutarate, and therefore, mitochondrial malfunction (in the stationary phase) may lead to effects on nitrogen balance and autophagy induction. Recently, it was reported that the onset of mitophagy in the stationary phase leads to the concomitant induction of retrograde pathway target genes (RTG) in an Aup1-dependent fashion (Journo, 2009). The authors have suggested that the function of Aup1p in mitophagy could be explained through its regulation of Rtg3-dependent transcription, but additional components will need to be identified in order to understand the specific mechanism by which defective (oxidative damage accumulating) mitochondria are targeted for degradation. One possibility is to test the involvement of mitochondrial Atg33p in Aup1-mediated mitophagy. Both Uth1p and Aup1p are mitochondrial proteins with localization in different mitochondrial compartments (the outer membrane or the intermembrane space, respectively) that are required for mitophagy, but unnecessary for starvation-induced bulk autophagic activity. Whereas Uth1p seems to be constitutively expressed in yeast cells under various growth conditions (logarithmical and stationary phase, starvation) (Camougrand, 2004), the Aup1p level peaks sharply at the beginning of the stationary phase, correlating with the onset of mitophagy (Tal, 2007). Interestingly, their effects on the physiological role of the process appear to be different: knockout of UTH1 results in increased viability of cells transferred from a nitrogen-replete medium to a nitrogen starvation medium, both containing lactate as a carbon source, or treated with rapamycin under the respiratory condition, while the absence of AUP1 results in decreased viability of cells in the late stationary phase during respiratory growth. Whether this difference is simply due to noncomparable assay conditions or whether it reflects some fundamental process addressing the roles of each protein remains ambiguous. Interestingly, neither Uth1p nor Aup1p has been found to be essential for the selective degradation of mitochondria in post-logarithmic-phase cells under respiratory conditions (Okamoto, 2009) or during nitrogen starvation in glucose-containing media after a shift from complete media supplemented with a respiratory carbon source (Kanki, 2009a). It is not known whether Uth1p and Aup1p interact with Atg32p, proposed to be a mitochondrial receptor specific for mitophagy, or some of the other autophagy-related proteins and directly mediate mitophagy. It has been proposed that there is a nonselective UTH1-independent form of mitophagy in yeast (Kiššová, 2007), but whether this is Atg32p dependent, and drives the bulk of mitophagy (by microautophagy), also remains to be examined. Induction and regulation of mitophagy Mitophagy and cell physiology There are several conditions shown in yeast that can induce mitophagy: nitrogen starvation, rapamycin treatment, stationary phase, intracellular redox imbalance, and some alteration of the mitochondrial function, such as a decrease in the membrane potential or oxidation of mitochondrial lipids (Fig. 1). Interestingly, selective mitochondrial degradation was discovered for the first time under conditions known to induce nonspecific autophagy: nitrogen starvation and rapamycin treatment (Kiššová, 2004). The absence of nitrogen does not induce mitophagy regularly/commonly, because a shift from a complete medium to starvation under sustained gluconeogenic conditions does not lead to mitophagy induction, contrary to the cells shifted to a starvation medium regardless of the carbon source (glucose or a respiratory substrate) after growth under the respiratory condition. It is important to remember that nonselective autophagy is induced to the same extent under both fermentative and respiratory conditions (Kiššová, 2004). Intriguingly, cells can possess several redundant mechanistically distinct/similar pathways to eliminate mitochondria, possibly converging to a common point, where alternative pathways can be utilized depending on the situation. Thus, vacuolar delivery of mitochondria in cells grown under respiratory conditions after their shift to a starvation medium with glucose is mediated by macroautophagy (Kanki, 2009a), while in starved cells under sustained respiratory conditions mitophagy is carried out in the microautophagic mode (Kiššová, 2007; Camougrand, 2008). Clearly, the inhibition of mitochondrial biogenesis is likely to interfere with mitochondrial clearance after the shift from a respiratory carbon source to a starvation under fermentative conditions and possibly has an effect on the mode of autophagy. A similar observation was reported in the case of peroxisomal degradation, which, depending on the carbon source in the medium, was effected through micropexophagy or macropexophagy (Sakai, 2006). The purpose of mitophagy after a shift from respiratory to fermentative conditions is without any doubt the removal of redundant organelles under new environmental conditions; the goal of such a specific process under starvation under respiratory conditions is not so obvious. There is a possibility that the degradation of some nonessential portion of mitochondria into molecular building blocks and their subsequent availability for biosynthesis means a lesser energetic expense than de novo synthesis for a cell. Starvation may affect mitochondrial metabolism, causing alterations that could trigger this process. The deletion of neither Atg32p nor Uth1p has been found to cause a defect in cell growth and cell death. Moreover, the absence of Uth1p rescues cells from starvation-induced death, suggesting that it is autophagy rather than mitophagy that is required for rescue from starvation. 1 View largeDownload slide Different conditions known to induce and regulate mitophagy in yeast. (a) Rapamycin induces early selective mitochondrial autophagy by the microautophagic pathway when added in media supplemented with a respiratory carbon source, and it is entirely prevented by the deletion of the UTH1 gene encoding the outer mitochondrial protein. Rapamycin-induced autophagy is accompanied by early production of ROS and early oxidation of mitochondrial lipids, where the inhibition of these oxidative events by the hydrophobic antioxidant resveratrol impairs mitophagy. The involvement of Atg32p in rapamycin-induced mitophagy is unclear and requires investigation. A shift from a complete medium containing a respiratory carbon source to starvation under a sustained respiratory condition (b), and in the presence of a fermentable sugar, glucose (c), induces early mitophagy. However, in the first case, mitochondria are removed by a direct absorption by the vacuolar membrane (micromitophagy), whereas in the second case, the process is carried out by an engulfment of the mitochondria into autophagosomes (macromitophagy). Under respiratory conditions (b), selective degradation of mitochondria does not appear in the absence of Uth1p, but some form of nonselective mitochondrial autophagy still takes place. It is not clear whether this process is Atg32p dependent, and remains to be examined. It is also not clear whether the lack of Uht1p itself (a, b) is the signal for mitophagy, or whether other mitochondrial or extramitochondrial proteins are involved in this process. The elimination of redundant mitochondria following the shift of cells into nitrogen starvation in the presence of glucose (c) is mediated by Atg32p, a protein proposed to be a mitochondrial receptor specific for mitophagy. (d) Mitochondrial dysfunctions including mitochondrial membrane potential reduction, lack/disruption of mitochondrial biogenesis, mitochondrial swelling, and fragmentation caused by the absence of individual mitochondrial proteins (Mdm38p, Fmc1p, Yme1p) trigger selective-elimination altered mitochondria by direct engulfment of organelles at the vacuolar surface (micromitophagy). Mdm38p-dependent mitophagy is mediated by Atg32p, and can be avoided by the inactivation of the pro-fusion DNM1 gene, or treatment with ionophore nigericin, respectively. In the case of Fmc1p- and Yme1p-dependent mitophagy, the role of Atg32p, if any, is not known. Mitophagy induced by the deletion of the YME1 gene can be suppressed by the absence of Ynt1p, a subunit of the 26S proteasome. (e) Entry into the stationary phase under respiratory conditions induces a massive vacuolar delivery and degradation of aged mitochondria through their specific engulfment by autophagosomes. This process is mediated by Atg32p; however, several other proteins were found to participate: outer mitochondrial membrane protein Atg33p, presumably required to detect or present aged mitochondria for degradation and intermembrane space, and protein Aup1, whose function in mitophagy involves the regulation of RTG induction. The possible interaction among all concerned proteins remains to be explored. Although both mitophagy and nonspecific autophagy can be induced under nitrogen starvation, rapamycin treatment, or some mitochondrial dysfunctions, these events might be regulated independently: the deletion of the DNM1 gene reduces mitophagy and a decrease in the intracellular glutathione (GSH) pool completely prevents mitophagy, but do not affect nonselective bulk autophagy. GSSG, glutathione disulfide. 1 View largeDownload slide Different conditions known to induce and regulate mitophagy in yeast. (a) Rapamycin induces early selective mitochondrial autophagy by the microautophagic pathway when added in media supplemented with a respiratory carbon source, and it is entirely prevented by the deletion of the UTH1 gene encoding the outer mitochondrial protein. Rapamycin-induced autophagy is accompanied by early production of ROS and early oxidation of mitochondrial lipids, where the inhibition of these oxidative events by the hydrophobic antioxidant resveratrol impairs mitophagy. The involvement of Atg32p in rapamycin-induced mitophagy is unclear and requires investigation. A shift from a complete medium containing a respiratory carbon source to starvation under a sustained respiratory condition (b), and in the presence of a fermentable sugar, glucose (c), induces early mitophagy. However, in the first case, mitochondria are removed by a direct absorption by the vacuolar membrane (micromitophagy), whereas in the second case, the process is carried out by an engulfment of the mitochondria into autophagosomes (macromitophagy). Under respiratory conditions (b), selective degradation of mitochondria does not appear in the absence of Uth1p, but some form of nonselective mitochondrial autophagy still takes place. It is not clear whether this process is Atg32p dependent, and remains to be examined. It is also not clear whether the lack of Uht1p itself (a, b) is the signal for mitophagy, or whether other mitochondrial or extramitochondrial proteins are involved in this process. The elimination of redundant mitochondria following the shift of cells into nitrogen starvation in the presence of glucose (c) is mediated by Atg32p, a protein proposed to be a mitochondrial receptor specific for mitophagy. (d) Mitochondrial dysfunctions including mitochondrial membrane potential reduction, lack/disruption of mitochondrial biogenesis, mitochondrial swelling, and fragmentation caused by the absence of individual mitochondrial proteins (Mdm38p, Fmc1p, Yme1p) trigger selective-elimination altered mitochondria by direct engulfment of organelles at the vacuolar surface (micromitophagy). Mdm38p-dependent mitophagy is mediated by Atg32p, and can be avoided by the inactivation of the pro-fusion DNM1 gene, or treatment with ionophore nigericin, respectively. In the case of Fmc1p- and Yme1p-dependent mitophagy, the role of Atg32p, if any, is not known. Mitophagy induced by the deletion of the YME1 gene can be suppressed by the absence of Ynt1p, a subunit of the 26S proteasome. (e) Entry into the stationary phase under respiratory conditions induces a massive vacuolar delivery and degradation of aged mitochondria through their specific engulfment by autophagosomes. This process is mediated by Atg32p; however, several other proteins were found to participate: outer mitochondrial membrane protein Atg33p, presumably required to detect or present aged mitochondria for degradation and intermembrane space, and protein Aup1, whose function in mitophagy involves the regulation of RTG induction. The possible interaction among all concerned proteins remains to be explored. Although both mitophagy and nonspecific autophagy can be induced under nitrogen starvation, rapamycin treatment, or some mitochondrial dysfunctions, these events might be regulated independently: the deletion of the DNM1 gene reduces mitophagy and a decrease in the intracellular glutathione (GSH) pool completely prevents mitophagy, but do not affect nonselective bulk autophagy. GSSG, glutathione disulfide. Mitophagy and redox imbalance Nonselective bulk autophagy and mitophagy are often induced by the same stimulus (nitrogen starvation and rapamycin), but it has been shown recently that these two events may be regulated independently (Bhatia-Kiššová & Camougrand, 2009; Deffieu, 2009). This conclusion was drawn based on the observation of cells starved for nitrogen in the presence or absence of various antioxidants after growth in a medium supplemented with a respiratory carbon source. Here, unlike other tested compounds, the addition of N-acetylcysteine (NAC) completely prevented mitophagy, while the general nonselective autophagic pathway was not affected. It has been demonstrated that the effect of NAC was not related to its ROS-scavenging properties, but rather to its fueling effect of the intracellular glutathione pool, which is indispensable for maintenance of the cellular redox balance (Deffieu, 2009). One of the critical factors regulating glutathione metabolism in living cells is the availability of its precursor l-cysteine, because only a small pool of this amino acid is available to sustain a much larger metabolically active glutathione pool. Although NAC can provide some benefit in preventing or reducing the toxicity related to moderate oxidative stress during nitrogen starvation, it was proposed that the availability of cysteine is a fundamental factor in the regulation of glutathione production. Apparently, an increase in the glutathione concentration in starved cells observed after NAC addition does not affect nonselective autophagy, but it has a remarkable effect on the delivery and degradation of mitochondria, as these processes are completely blocked. By manipulating glutathione, it has been possible to identify the relationships between the redox status of the cells and mitophagy. The hypothesis that redox imbalance and intracellular glutathione content modulate mitophagy induction also confirms the observation showing that the addition of ethacrynic acid, known to decrease the glutathione pool in growth medium, accelerates mitophagy in cells when they reach the stationary phase (Deffieu, 2009). The stimulation of glutathione synthesis (by NAC) restores NAD(P)H/NAD(P) ratios and may accommodate significant changes in mitochondrial status, which would possibly relieve the requirement for mitochondria elimination. In fact, no selective mitophagy has ever been observed on glucose-grown cells (Kiššová, 2007), where the activity of the mitochondria, and the potential danger they might represent, is low. Mitophagy might be finely tuned by subtle changes in the concentration and compartmentalization of glutathione or regulated by thiol-containing proteins targeted by glutathione, and additional investigations are needed to refine these critical points. Moreover, the fact that glutathione is a known powerful cellular antioxidant, and at the same time decreases mitophagy, fits the notion that autophagy is specifically overactivated in the face of an injury to a particular cellular component. In mammals, it has been shown that a mitochondrial injury in CoQ-deficient fibroblasts is accompanied by an increase in mitochondrial degradation by mitophagy, which can be abolished by antioxidants (Rodríguez-Hernández, 2009). Mitophagy and mitochondrial dysfunctions In yeast, mitophagy can be induced under a nutrient-limited condition as an attempt to eliminate superfluous or eventually altered mitochondria, but was also reported to represent a cellular response designed to face stress conditions causing physiological mitochondrial dysfunction. In one study, the occurrence of the preferential degradation of mitochondria was reported as a consequence of impairing the mitochondrial electrochemical transmembrane potential (ΔΨm) and/or the lack of mitochondrial biogenesis, resulting from anaerobic and heat stress growth of an FMC1 null mutant in fermentable glucose-containing media (Priault, 2005). Under these conditions, the collapse of ΔΨm was due to the accumulation of aggregates of a dysfunctional F1 ATPase subunit, and the inability to use glycolytic ATP for the membrane potential maintenance, which leads to cell death. Based on electron-microscopy observations, both macro- and microautophagy were triggered under these conditions, and to understand which pathway mediated mitochondrial turnover will require further work. Another study has reported that alterations in mitochondrial ion homeostasis caused by the inactivation of the K+/H+ exchanger Mdm38p induced both autophagy and selective degradation of mitochondria by microautophagy (Nowikovsky, 2007). The deletion of MDM38 caused pleiotropic effects including mitochondrial swelling, loss of ΔΨm, fragmentation, and reduction of cell growth on nonfermentable substrates; however, the results indicate that K+/H+ exchange activity is primarily responsible for mediating mitophagy. Cells lacking Mdm38p were more likely to die in a stationary phase. It is not known whether this form of death was due to mitophagy/autophagy or whether there was a specific K+/H+ exchange defect that is not known. Recently, it was shown that Mdm38p-dependent mitophagy is mediated by Atg32p (Kanki, 2009a). Based on these data, an alteration in the mitochondrial membrane potential can induce mitophagy in yeast. However, the fact that (1) the inactivation of the profission DNM1 gene avoided Mdm38p-mediated mitophagy, although mitochondria still have reduced ΔΨm (Nowikovsky, 2007) and (2) chemical disruption of ΔΨm does not induce autophagy or mitophagy (Kiššová, 2004; Kanki & Klionsky, 2008) suggests that in yeast, contrary to mammals, a change in the ΔΨm potential may influence, but may not be sufficient for mitophagy induction. In light of these results, mitophagy can serve as a possible cellular surveillance over the control of mitochondrial quality or as a final program initiated when cells cannot recuperate from mitochondrial damage. In addition to the cases described above, the implication of mitochondrial fission in the mitophagic process has been reported in several other studies. The addition of rapamycin or nitrogen starvation induced fragmentation of the mitochondrial network, followed by selective mitochondrial degradation, but the inhibition of mitochondrial lipid oxidation (Kiššová, 2006a) or the maintenance of the cellular redox balance by glutathione pool renewal (Deffieu, 2009) that prevents mitophagy did not prevent the initial alteration of the mitochondrial network. In mammals, the inhibition of the fission machinery through DRP1 or FIS1 inactivation decreased mitochondrial autophagy, and resulted in the accumulation of oxidized mitochondrial proteins (Twig, 2008; Dagda, 2009). Furthermore, these findings suggest that fission, followed by selective fusion segregates dysfunctional mitochondria, allowing their removal by autophagy. Recently, DNM1 has also been identified in one screen as a gene whose absence reduced mitophagy in yeast (Kanki, 2009b). Actin and other cytoskeletal proteins act as binding partners for Dnm1p; therefore, it is not surprising that the actin cytoskeleton has been found to be required for some selective types of autophagy (Reggiori & Klionsky, 2005). Further analyses are needed to test the involvement of actin in the regulation of mitophagy. Mitophagy and aging Incubation of yeast cells during a prolonged stationary (late logarithmic) phase, especially in the case of growth under aerobic conditions, gives rise to the accumulation of damaged mitochondria. They can generate ROS, release cell death-inducing factors such as cytochrome c into the cytosol, or generally burden the metabolic machinery of the cell by decreasing the efficiency of ATP generation. Thus, the ability to recognize and degrade such impaired mitochondria is a vital task in cells. It has been shown that these conditions induce massive and specific autophagic mitochondrial removal, and several genes have been identified as key players in this process (Tal, 2007; Kanki & Klionsky, 2008; Deffieu, 2009; Kanki, 2009a, b; Okamoto, 2009). The function of one protein required for mitophagy under this condition, Aup1p, is required for the survival of cells through a prolonged stationary phase. The absence of another one (Atg32p) does not have a discernible effect on cell viability, and the lack of another involved protein (Uth1p) even improves cell survival. This suggests that each protein can manage a different function in this process, and it is not known whether these proteins occur in a common or a linked generic pathway. Mitochondria under these conditions seemed to be removed by a macroautophagic pathway, including the generation of autophagosomes containing only selected organelles, mitophagosome (Kanki, 2009a; Okamoto, 2009). Mitophagy, ROS, and cell death It has been proposed that although autophagy is actually a prosurvival process, an abnormally high level of autophagy might be responsible for cell death (Kundu & Thompson, 2005; Pattingre, 2005). The treatment of yeast cells with rapamycin induces autophagy even under nutrition-rich conditions (Cardenas, 1999) and leads to growth arrest and surprisingly rapid loss of viability in both the respiratory and the fermentative case (Kiššová, 2004). This drug was also found to induce early selective mitochondrial autophagy by the microautophagic pathway, when added in media supplemented with lactate, and it was entirely prevented by the deletion of the UTH1 gene (Camougrand, 2004; Kiššová, 2004). Further studies have revealed that rapamycin-induced autophagy was accompanied by the early production of ROS and by the early oxidation of mitochondrial lipids. Inhibition of these oxidative effects by the hydrophobic antioxidant resveratrol largely impaired autophagy of both cytosolic proteins and mitochondria, and delayed subsequent cell death, suggesting that mitochondrial oxidation events may play a crucial role in the regulation of autophagy (Kiššová, 2006a). There is evidence that autophagy can be regulated by ROS as supported by data derived from studies in HeLa cells (Scherz-Shouval, 2007), where it was demonstrated that starvation stimulates ROS production, namely H2O2, which was essential for autophagy. Furthermore, the cysteine protease hsAtg4 was identified as a direct target for oxidation by H2O2. Another study has reported that inactivation of catalase induced programmed cell death accompanied by autophagy and elimination of altered mitochondria (Yu, 2006). Mitochondrial lipid oxidation is not only an indicator of mitochondrial dysfunction, but can also be a hallmark for altered mitochondria because, in contrast to ROS, oxidized lipids are not expected to diffuse rapidly throughout the cell, including to other mitochondria, especially if the mitochondrial network is fragmented as it occurs early during autophagy (Kiššová, 2004, 2006a). The combination of mitochondria fragmentation and mitochondrial lipid oxidation might together be an adequate signal indicating that the autophagic machinery should be activated. The fact that the inhibition of lipid oxidation by hydrophobic antioxidants limits autophagy lends further support to a crucial role of membrane lipid oxidation as a trigger for the degradation of altered mitochondria. The poor preventative ability of hydrophilic ROS scavengers suggests that the role of soluble ROS in the signaling remains marginal. The impact of mitophagy on cell survival under this peculiar condition when autophagy itself seems to cause cell death remains unknown. It is also not known whether Atg32p mediates rapamycin-induced mitophagy. Genomic screens for yeast mutants defective in selective mitochondria autophagy have revealed 53 mitophagy-related genes where absence resulted in a partial or a complete block of the process (Kanki, 2009a, b; Okamoto, 2009; Kanki & Klionsky, 2010). In addition to 30 mutants that are known to be defective in autophagy and/or the Cvt pathway, another 23 cytosolic and mitochondrial mutants obtained have not been implicated and are involved in diverse cellular processes. Future analyses can lead to a better understanding of the key players in the mechanism(s) and the regulation of mitophagy. Conclusion Mitochondria form complex and dynamic networks within cells and are, in fact, a single population when it comes to exchange of genetic information in a cell (Nakada, 2001). However, it is possible that at a certain level/amount of mitochondrial injury, there is no complementation of function by the remaining ‘healthy’ mitochondria, and the cell wants to eliminate damaged organelles. Based on the latest data, autophagy-dependent degradation of mitochondria is a fundamental process conserved from yeast to humans. It is conceivable that mitochondria are the primary target of selective autophagy, because they accumulate oxidative damage due to their own byproducts, ROS, and that clearance of dysfunctional mitochondria is important for organelle quality control. Consistent with this idea, the loss of mitochondrial functions promotes organelle degradation and defects in autophagy cause mitochondrial abnormalities, the latter of which might ultimately be associated with cell aging and death. Interestingly, Parkin and PINK1, both Parkinson's disease-associated proteins, promote elimination of impaired mitochondria, which highlights a possible link between mitophagy and neurodegenerative disorders (Narendra, 2008, 2010; Dagda & Chu, 2009; Dagda, 2009; Vives-Bauza, 2010). Moreover, complete autophagic mitochondrial clearance is essential for erythrocyte and reticulocyte maturation, implying a role of mitophagy in cell differentiation (Zhang & Ney, 2010). Accumulation of dysfunctional mitochondria also causes mitochondrial autophagy in yeast. In this organism, mitophagy also takes place in cells during starvation or cultivation in the late stationary phase under respiratory conditions. Furthermore, some results support the view that activation of mitophagy, as a process that protects against mitochondrial alteration, is a means to convert a necrotic form of death into a regulated form of death (Kiššová, 2006b). These reported data indicate that induction and regulation of mitophagy are very complex processes that can exhibit modifications in the cell's attempt to assume the most favorable position in accommodating the different physiological states of the cell and changing environment. Further understanding of the molecular mechanisms underlying the regulation and selectivity of the mitophagic process may prove to be relevant to therapeutic strategies in mitochondrial-related disorders. The riveting challenge for scientists also includes the questions to what extent can mitochondria be removed from cells to still preserve normal cell functioning and what are the components and signalling pathway(s) involved in monitoring and evaluation in cells? Acknowledgements This work was supported in part by grants from Slovak Ministry of Education Contract VEGA1/0264/08, Science and Technology Assistance Agency Contract APVV-0024-07, the CNRS, the Université de Bordeaux 2, the Conseil Régional d'Aquitaine, and Association pour la Reserche contre le Cancer grant 3812. The France/Slovakia collaboration was supported by Egide ECO-NET 10187VF. References Ashford TP Porter KR ( 1962) Cytoplasmic components in hepatic cell lysosomes. J Cell Biol  12: 198– 202. Google Scholar CrossRef Search ADS PubMed  Bandara PDS Flattery O'Brien JA Grant CM Dawes IW ( 1998) Involvement of the Saccharomyces cerevisiae UTH1 gene in the oxidative stress response. Curr Genet  34: 259– 268. Google Scholar CrossRef Search ADS PubMed  Beaulaton J Lockshin RA ( 1977) Ultrastructural study of the normal degeneration of the intersegmental muscles of Anthereae polyphemus and Manduca sexta (Insecta, Lepidoptera) with particular reference of cellular autophagy. J Morphol  154: 39– 57. Google Scholar CrossRef Search ADS PubMed  Bhatia-Kiššová I Camougrand N ( 2009) Glutathione participates in the regulation of mitophagy in yeast. Autophagy  5: 1– 2. Camougrand N Grelaud-Coq A Marza E Priault M Bessoule JJ Manon S ( 2003) The product of the UTH1 gene, required for Bax-induced cell death in yeast, is involved in the response to rapamycin. Mol Microbiol  47: 495– 506. Google Scholar CrossRef Search ADS PubMed  Camougrand N Kiššová I Velours G Manon S ( 2004) Uth1p: a yeast mitochondrial protein at the crossroads of stress, degradation and cell death. FEMS Yeast Res  5: 133– 140. Google Scholar CrossRef Search ADS PubMed  Camougrand N Kiššová I Salin B Devenish RJ ( 2008) Monitoring mitophagy in yeast. Method Enzymol  451: 89– 107. Campbell CL Thorsness PE ( 1998) Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments. J Cell Sci  111: 2455– 2464. Google Scholar PubMed  Cardenas ME Cutler NS Lorenz MC Di Como J Heitman J ( 1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev  13: 3271– 3279. Google Scholar CrossRef Search ADS PubMed  Clark SL Jr ( 1957) Cellular differentiation in the kidneys of newborn mice studies with the electron microscope. J Biophys Biochem Cy  3: 349– 362. Google Scholar CrossRef Search ADS   Dagda RK Chu CT ( 2009) Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis. J Bioenerg Biomembr  41: 473– 479. Google Scholar CrossRef Search ADS PubMed  Dagda RK Cherra SJ Kulich SM Tandon A Park D Chu CT ( 2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem  284: 13843– 13855. Google Scholar CrossRef Search ADS PubMed  Decker RS Wildenthal K ( 1980) Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol  98: 425– 444. Google Scholar PubMed  Deffieu M Bhatia-Kiššová I Salin B Galinier A Manon S Camougrand N ( 2009) Glutathione participates in the regulation of mitophagy in yeast. J Biol Chem  284: 14828– 14837. Google Scholar CrossRef Search ADS PubMed  Elmore SP Qian T Grissom SF Lemasters JJ ( 2001) The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J  15: 2286– 2287. Google Scholar PubMed  Farre CD Krick R Subramani S Thumm M ( 2009) Turnover of organelles by autophagy in yeast. Curr Opin Cell Biol  21: 522– 530. Google Scholar CrossRef Search ADS PubMed  Gey U Czupalla C Hoflack B Rodel G Krause-Buchholz U ( 2008) Yeast pyruvate dehydrogenase complex is regulated by a concerted activity of two kinases and two phosphatases. J Biol Chem  283: 9759– 9767. Google Scholar CrossRef Search ADS PubMed  Hamasaki M Noda T Baba M Ohsumi Y ( 2005) Starvation triggers the delivery of the endoplasmic reticulum to the vacuole via autophagy in yeast. Traffic  6: 56– 65. Google Scholar CrossRef Search ADS PubMed  Heynen MJ Verwilghen RL ( 1982) A quantitative ultrastructural study of normal rat erythroblasts and reticulocytes. Cell Tissue Res  224: 397– 408. Google Scholar CrossRef Search ADS PubMed  Huang WP Klionsky DJ ( 2002) Autophagy in yeast: a review of the molecular machinery. Cell Struct Funct  27: 409– 420. Google Scholar CrossRef Search ADS PubMed  Jazwinski SM ( 2005) Yeast longevity and aging – the mitochondrial connection. Mech Ageing Dev  126: 243– 248. Google Scholar CrossRef Search ADS PubMed  Journo D Mor A Abeliovich H ( 2009) Aup1-mediated regulation of Rtg3 during mitophagy. J Biol Chem  284: 35885– 35895. Google Scholar CrossRef Search ADS PubMed  Kanki T Klionsky DJ ( 2008) Mitophagy in yeast occurs through a selective mechanism. J Biol Chem  283: 32386– 32393. Google Scholar CrossRef Search ADS PubMed  Kanki T Klionsky DJ ( 2010) The molecular mechanism of mitochondria autophagy in yeast. Mol Microbiol  75: 795– 800. Google Scholar CrossRef Search ADS PubMed  Kanki T Wang K Baba M et al.   ( 2009a) A genomic screen for yeast mutants defective in selective mitochondria autophagy. Mol Biol Cell  20: 4730– 4738. Google Scholar CrossRef Search ADS   Kanki T Wang K Cao Y Baba M Klionsky DJ ( 2009b) Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell  17: 98– 109. Google Scholar CrossRef Search ADS   Kennedy BK Austriaco NR Zhang J Guarente L ( 1995) Mutation in the silencing gene can delay aging in S. cerevisiae. Cell  80: 485– 496. Google Scholar CrossRef Search ADS PubMed  Kiel JA Komduur JA Van der Klei IJ Veenhuis M ( 2003) Macropexophagy in Hansenula polymorpha: facts and views. FEBS Lett  549: 1– 6. Google Scholar CrossRef Search ADS PubMed  Kim I Rodriguez-Enriquez S Lemasters JJ ( 2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys  462: 245– 253. Google Scholar CrossRef Search ADS PubMed  Kim J Kamada Y Stromhaug PE Guan J Hefner-Gravink A Baba M Scott SV Ohsumi Y Dunn WA Jr Klionsky DJ ( 2001) Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole. J Cell Biol  153: 381– 396. Google Scholar CrossRef Search ADS PubMed  Kiššová I Deffieu M Manon S Camougrand N ( 2004) Uth1p is involved in the autophagic degradation of mitochondria. J Biol Chem  279: 39068– 39074. Google Scholar CrossRef Search ADS PubMed  Kiššová I Deffieu M Samokhvalov V Velours G Bessoule JJ Manon S Camougrand N ( 2006a) Lipid oxidation and autophagy in yeast. Free Radical Bio Med  1: 1655– 1661. Google Scholar CrossRef Search ADS   Kiššová I Plamondon LT Brisson L Priault M Renouf V Schaeffer J Camougrand N Manon S ( 2006b) Evaluation of the roles of apoptosis, autophagy, and mitophagy in the loss of plating efficiency induced by Bax expression in yeast. J Biol Chem  281: 36187– 36197. Google Scholar CrossRef Search ADS   Kiššová I Salin B Schaeffer J Bhatia S Manon S Camougrand N ( 2007) Selective and non-selective autophagic degradation of mitochondria in yeast. Autophagy  3: 329– 336. Google Scholar CrossRef Search ADS PubMed  Kraft C Deplazes A Sohrmann M Peter M ( 2008) Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nat Cell Biol  10: 602– 610. Google Scholar CrossRef Search ADS PubMed  Kundu M Thompson CB ( 2005) Macroautophagy versus mitochondrial autophagy: a question of fate? Cell Death Differ  12: 1484– 1489. Google Scholar CrossRef Search ADS PubMed  Lemasters JJ ( 2005) Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuv Res  8: 3– 5. Google Scholar CrossRef Search ADS   Lemasters JJ Nieminen AL Qian T et al.   ( 1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta  1366: 177– 196. Google Scholar CrossRef Search ADS PubMed  Nair U Klionsky DJ ( 2005) Molecular mechanisms and regulation of specific and nonspecific autophagy pathways in yeast. J Biol Chem  280: 41785– 41788. Google Scholar CrossRef Search ADS PubMed  Nakada K Inoue K Ono T Isobe K Ogura A Goto YI Nonaka I Hayashi JI ( 2001) Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med  7: 934– 940. Google Scholar CrossRef Search ADS PubMed  Narendra D Tanaka A Suen DF Youle RJ ( 2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol  183: 795– 803. Google Scholar CrossRef Search ADS PubMed  Narendra DP Jin SM Tanaka A Suen DF Gautier CA Shen J Cookson MR Youle RJ ( 2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol  8: e1000298. Nowikovsky K Reipert S Devenish RJ Schweyen RJ ( 2007) Mdm38 protein depletion causes loss of mitochondrial K+/H+exchange activity, osmotic swelling and mitophagy. Cell Death Differ  14: 1647– 1656. Google Scholar CrossRef Search ADS PubMed  Okamoto K Kondo-Okamoto N Ohsumi Y ( 2009) Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autiophagy. Dev Cell  17: 87– 97. Google Scholar CrossRef Search ADS PubMed  Pan X Roberts P Chen Y Kvam E Shulga N Huang K Lemmon S Goldfarb DS ( 2000) Nucleus–vacuole junctions in Saccharomyces cerevisiae are formed through the direct interaction of Vac8p with Nvj1p. Mol Biol Cell  11: 2445– 2457. Google Scholar CrossRef Search ADS PubMed  Pattingre S Tassa A Qu X Garuti R Liang XH Mizushima N Packer M Schneider MD Levine B ( 2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell  122: 927– 939. Google Scholar CrossRef Search ADS PubMed  Priault M Salin B Schaeffer J Vallette FM Di Rago JP Martinou JC ( 2005) Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ  12: 1613– 1621. Google Scholar CrossRef Search ADS PubMed  Reggiori F Klionsky DJ ( 2005) Autophagosomes: biogenesis from scratch? Curr Opin Cell Biol  17: 415– 422. Google Scholar CrossRef Search ADS PubMed  Roberts P Moshitch-Moshkovitz S Kvam E O'Toole E Winey M Goldfarb DS ( 2003) Piecemal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell  14: 129– 141. Google Scholar CrossRef Search ADS PubMed  Rodríguez-Hernández A Cordero MD Salviati L Artuch R Pineda M Briones P Gomez-Izquierdo L Cotan D Navas P Sanchez-Alcazar JA ( 2009) Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy  5: 19– 32. Google Scholar CrossRef Search ADS PubMed  Sakai Y Koller A Rangell LK Keller GA Subramani S ( 1998) Peroxisome degradation by microautophagy in Pichia pastoris: identification of specific steps and morphological intermediates. J Cell Biol  141: 625– 636. Google Scholar CrossRef Search ADS PubMed  Sakai Y Oku M Van Der Klei IJ Kiel JA ( 2006) Pexophagy: autophagic degradation of peroxisomes. Biochim Biophys Acta  1763: 1767– 1775. Google Scholar CrossRef Search ADS PubMed  Sandoval H Thiagarajan P Dasgupta SK Schumacher A Prchal JT Chen M Wang J ( 2008) Essential role for Nix in autophagic maturation of erythroid cells. Nature  454: 232– 235. Google Scholar CrossRef Search ADS PubMed  Sanz A Pamplona R Barja G ( 2006) Is the mitochondrial free radical theory of aging intact? Antioxid Redox Sign  8: 582– 599. Google Scholar CrossRef Search ADS   Scherz-Shouval R Shvets E Fass E Shorer H Gil L Elazar Z ( 2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J  26: 1749– 1760. Google Scholar CrossRef Search ADS PubMed  Schweers RL Zhang J Randall MS et al.   ( 2007) NIX is required for programmed mitochondrial clearance during reticulocyte maturation. P Natl Acad Sci USA  104: 19500– 19505. Google Scholar CrossRef Search ADS   Takeshige K Baba M Tsuboi S Noda T Ohsumi Y ( 1992) Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol  119: 301– 311. Google Scholar CrossRef Search ADS PubMed  Tal R Winter G Ecker N Klionsky DJ Abeliovich H ( 2007) Aup1p, a yeast mitochondrial protein phosphatase homolog, is required for efficient stationary phase mitophagy and cell survival. J Biol Chem  282: 5617– 5624. Google Scholar CrossRef Search ADS PubMed  Terman A Gustafsson B Brunk UT ( 2006) Mitochondrial damage and intralysosomal degradation in cellular aging. Mol Aspects Med  27: 471– 482. Google Scholar CrossRef Search ADS PubMed  Tolkovsky AM ( 2009) Mitophagy. Biochim Biophys Acta  1793: 1508– 1515. Google Scholar CrossRef Search ADS PubMed  Tolkovsky AM Xue L Fletcher GC Borutaite V ( 2002) Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease? Biochimie  84: 233– 240. Google Scholar CrossRef Search ADS PubMed  Tsukada M Ohsumi Y ( 1993) Isolation and characterization of autophagy-defective mutants of Sacchaaromyces cerevisiae. FEBS  33: 169– 174. Google Scholar CrossRef Search ADS   Twig G Elorza A Molina AJ et al.   ( 2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J  27: 433– 446. Google Scholar CrossRef Search ADS PubMed  Vives-Bauza C Zhou C Huang Y et al.   ( 2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. P Natl Acad Sci USA  107: 378– 383. Google Scholar CrossRef Search ADS   Xue L Fletcher GC Tolkovsky AM ( 1999) Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci  14: 180– 198. Google Scholar CrossRef Search ADS PubMed  Xue L Fletcher GC Tolkovsky AM ( 2001) Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr Biol  11: 361– 365. Google Scholar CrossRef Search ADS PubMed  Yu BP Chung HY ( 2006) Adaptive mechanisms to oxidative stress during aging. Mech Ageing Dev  127: 436– 443. Google Scholar CrossRef Search ADS PubMed  Yu L Wan F Dutta S Welsh S Liu Z Freundt E Baehrecke EH Lenardo M ( 2006) Autophagic programmed cell death by selective catalase degradation. P Natl Acad Sci USA  103: 4952– 4957. Google Scholar CrossRef Search ADS   Zhang J Ney PA ( 2010) Reticulocyte mitophagy: monitoring mitochondrial clearance in a mammalian model. Autophagy  6: 405– 408. Google Scholar CrossRef Search ADS PubMed  Zhang Y Qi H Taylor R Xu W Liu LF Jin S ( 2007) The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy  3: 337– 346. Google Scholar CrossRef Search ADS PubMed  © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved
TI - Mitophagy in yeast: actors and physiological roles
JF - FEMS Yeast Research
DO - 10.1111/j.1567-1364.2010.00659.x
DA - 2010-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/mitophagy-in-yeast-actors-and-physiological-roles-ffLobicVUq
SP - 1023
EP - 1034
VL - 10
IS - 8
DP - DeepDyve
ER -