Self and Nonself: How Autophagy Targets Mitochondria and Bacteria
2014; Cell Press; Volume: 15; Issue: 4 Linguagem: Inglês
10.1016/j.chom.2014.03.012
ISSN1934-6069
AutoresFelix Randow, Richard J. Youle,
Tópico(s)Calcium signaling and nucleotide metabolism
ResumoAutophagy is an evolutionarily conserved pathway that transports cytoplasmic components for degradation into lysosomes. Selective autophagy can capture physically large objects, including cell-invading pathogens and damaged or superfluous organelles. Selectivity is achieved by cargo receptors that detect substrate-associated "eat-me" signals. In this Review, we discuss basic principles of selective autophagy and compare the "eat-me" signals and cargo receptors that mediate autophagy of bacteria and bacteria-derived endosymbionts—i.e., mitochondria. Autophagy is an evolutionarily conserved pathway that transports cytoplasmic components for degradation into lysosomes. Selective autophagy can capture physically large objects, including cell-invading pathogens and damaged or superfluous organelles. Selectivity is achieved by cargo receptors that detect substrate-associated "eat-me" signals. In this Review, we discuss basic principles of selective autophagy and compare the "eat-me" signals and cargo receptors that mediate autophagy of bacteria and bacteria-derived endosymbionts—i.e., mitochondria. The maintenance of cellular homeostasis requires the controlled elimination of cellular components. Autophagy is of particular importance in this respect, since, in contrast to the proteasome and other cytosolic degradation machinery, autophagy can achieve the degradation of physically large and chemically diverse substrates including protein aggregates, cellular organelles, and even cytosol-invading pathogens (Deretic et al., 2013Deretic V. Saitoh T. Akira S. Autophagy in infection, inflammation and immunity.Nat. Rev. Immunol. 2013; 13: 722-737Crossref PubMed Scopus (1336) Google Scholar, Levine et al., 2011Levine B. Mizushima N. Virgin H.W. Autophagy in immunity and inflammation.Nature. 2011; 469: 323-335Crossref PubMed Scopus (2428) Google Scholar, Mizushima and Komatsu, 2011Mizushima N. Komatsu M. Autophagy: renovation of cells and tissues.Cell. 2011; 147: 728-741Abstract Full Text Full Text PDF PubMed Scopus (3947) Google Scholar, Randow and Münz, 2012Randow F. Münz C. Autophagy in the regulation of pathogen replication and adaptive immunity.Trends Immunol. 2012; 33: 475-487Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Evolutionarily, autophagy is thought to have originated as a starvation-induced pathway that nonselectively degrades cytosolic compounds into building blocks and thereby provides energy and maintains essential anabolic processes even when external resources are limiting. How autophagy engulfs specific cargo is a particularly interesting problem for which much progress has been achieved recently. In this Review, we will discuss and compare how autophagy eliminates cytosol-invading bacteria and damaged or excess mitochondria, a conundrum conceptually related to the immune system's task of distinguishing self from non-self and further complicated by the evolutionary relatedness of mitochondria and bacteria. We therefore will focus on how "eat-me" signals and cargo receptors provide specificity for these cellular processes. Macroautophagy (hereafter autophagy) is an evolutionarily conserved cellular activity that delivers cytosolic material into double-membrane vesicles, called autophagosomes, that eventually fuse with late endosomes or lysosomes (Mizushima and Komatsu, 2011Mizushima N. Komatsu M. Autophagy: renovation of cells and tissues.Cell. 2011; 147: 728-741Abstract Full Text Full Text PDF PubMed Scopus (3947) Google Scholar). Autophagosome biogenesis proceeds along a stereotypical path (Weidberg et al., 2011Weidberg H. Shvets E. Elazar Z. Biogenesis and cargo selectivity of autophagosomes.Annu. Rev. Biochem. 2011; 80: 125-156Crossref PubMed Scopus (373) Google Scholar). Initially a crescent-shaped double membrane forms, which is known as an isolation membrane or phagophore. The phagophore subsequently grows and sequesters cytosolic material, which, upon fusion of the phagophore edge, becomes fully enclosed inside the autophagosome. Autophagosomes finally mature into organelles competent to fuse with lysosomes, whereupon lysosomal enzymes degrade the autophagosome contents including the inner autophagosomal membrane. Autophagosome biogenesis requires the coordinated action of about 15 "core" autophagy-related or ATG genes, several of which associate into protein complexes (Mizushima et al., 2011Mizushima N. Yoshimori T. Ohsumi Y. The role of Atg proteins in autophagosome formation.Annu. Rev. Cell Dev. Biol. 2011; 27: 107-132Crossref PubMed Scopus (2161) Google Scholar). ATG9, the only polytopic transmembrane protein essential for autophagy, and the ULK complex are independently recruited to nascent phagophores upon amino acid starvation. Then ULK kinase activity recruits the VPS34 lipid kinase complex that produces membrane patches rich in phosphatidylinositol 3-phosphate (PI(3)P) (Russell et al., 2013Russell R.C. Tian Y. Yuan H. Park H.W. Chang Y.-Y. Kim J. Kim H. Neufeld T.P. Dillin A. Guan K.-L. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase.Nat. Cell Biol. 2013; 15: 741-750Crossref PubMed Scopus (1060) Google Scholar). Phagophores are generated de novo from these PI(3)P-enriched domains at ER-mitochondria contact sites under the control of PI(3)P-binding proteins such as WIPI1/2 (Hamasaki et al., 2013Hamasaki M. Furuta N. Matsuda A. Nezu A. Yamamoto A. Fujita N. Oomori H. Noda T. Haraguchi T. Hiraoka Y. et al.Autophagosomes form at ER-mitochondria contact sites.Nature. 2013; 495: 389-393Crossref PubMed Scopus (1192) Google Scholar). Phagophore biogenesis requires extensive membrane remodeling, including the formation of ER-derived, PI(3)P-enriched omegasomes marked by DFCP1, another PI(3)P-binding protein (Axe et al., 2008Axe E.L. Walker S.A. Manifava M. Chandra P. Roderick H.L. Habermann A. Griffiths G. Ktistakis N.T. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum.J. Cell Biol. 2008; 182: 685-701Crossref PubMed Scopus (1351) Google Scholar). The elongation and ultimate closure of phagophores relies on the conjugation of two ubiquitin-like proteins, ATG12 and ATG8, to ATG5 and the lipid phosphatidyl ethanolamine (PE), respectively (Mizushima et al., 2011Mizushima N. Yoshimori T. Ohsumi Y. The role of Atg proteins in autophagosome formation.Annu. Rev. Cell Dev. Biol. 2011; 27: 107-132Crossref PubMed Scopus (2161) Google Scholar). To catalyze the lipidation of ATG8 the ATG12∼ATG5 conjugate associates with ATG16 into an E3-like enzyme complex, whose localization, together with more upstream components, specifies the site of autophagosome biogenesis. While yeasts encode only a single ATG8 gene, humans harbor six orthologs that cluster into the LC3 and GABARAP subfamilies (Weidberg et al., 2011Weidberg H. Shvets E. Elazar Z. Biogenesis and cargo selectivity of autophagosomes.Annu. Rev. Biochem. 2011; 80: 125-156Crossref PubMed Scopus (373) Google Scholar). Membrane-associated LC3/GABARAP provide docking sites for receptors that deliver specific cargo to phagophores during selective autophagy (Boyle and Randow, 2013Boyle K.B. Randow F. The role of 'eat-me' signals and autophagy cargo receptors in innate immunity.Curr. Opin. Microbiol. 2013; 16: 339-348Crossref PubMed Scopus (139) Google Scholar, Johansen and Lamark, 2011Johansen T. Lamark T. Selective autophagy mediated by autophagic adapter proteins.Autophagy. 2011; 7: 279-296Crossref PubMed Scopus (1295) Google Scholar). Starvation-induced autophagy is a nonselective process that degrades randomly engulfed cytosolic components in order to fuel the cell in lean times and to provide building blocks for anabolic activities. In contrast, the task of selective autophagy is the elimination of specific cytosolic objects in the maintenance of cellular homeostasis, such as bacteria, damaged organelles, or protein aggregates (Weidberg et al., 2011Weidberg H. Shvets E. Elazar Z. Biogenesis and cargo selectivity of autophagosomes.Annu. Rev. Biochem. 2011; 80: 125-156Crossref PubMed Scopus (373) Google Scholar). Selectivity is achieved by receptors that enforce physical proximity between cargo and autophagy machinery due to simultaneous binding of "eat-me" signals on the prospective cargo and LC3/GABARAP on phagophores (Boyle and Randow, 2013Boyle K.B. Randow F. The role of 'eat-me' signals and autophagy cargo receptors in innate immunity.Curr. Opin. Microbiol. 2013; 16: 339-348Crossref PubMed Scopus (139) Google Scholar, Johansen and Lamark, 2011Johansen T. Lamark T. Selective autophagy mediated by autophagic adapter proteins.Autophagy. 2011; 7: 279-296Crossref PubMed Scopus (1295) Google Scholar). Cargo receptors have emerged by convergent evolution and subsequent gene duplication events; currently known are at least five members (p62 and its paralog NBR1, NDP52 and its paralog T6BP, and optineurin) (Figure 1). The interaction of cargo receptors with LC3/GABARAP relies on the formation of an intermolecular β sheet to which the cargo receptor contributes a single strand, the so-called LC3-interacting region (LIR). Negatively charged residues adjacent to the LIR motif contribute to the interaction, sometimes in a phosphorylation-dependent and therefore regulable manner (Wild et al., 2011Wild P. Farhan H. McEwan D.G. Wagner S. Rogov V.V. Brady N.R. Richter B. Korac J. Waidmann O. Choudhary C. et al.Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.Science. 2011; 333: 228-233Crossref PubMed Scopus (958) Google Scholar). Cargo receptors displaying consensus variants of the LIR motif W/FxxI/L/V interact promiscuously with most if not all LC3/GABARAP family members. However, specificity for individual LC3/GABARAP proteins can be provided by more extreme variants of the LIR motif, such as the ILVV peptide occurring in NDP52, which binds selectively to LC3C (von Muhlinen et al., 2012von Muhlinen N. Akutsu M. Ravenhill B.J. Foeglein A. Bloor S. Rutherford T.J. Freund S.M.V. Komander D. Randow F. LC3C, Bound Selectively by a Noncanonical LIR Motif in NDP52, Is Required for Antibacterial Autophagy.Mol. Cell. 2012; 48: 329-342Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). This selectivity of NDP52 for LC3C entrusts an essential role to LC3C in NDP52-dependent selective autophagy. Why NDP52 in contrast to other cargo receptors relies selectively on LC3C remains unknown but preferential binding could enable NDP52 to control a specific step of autophagosome biogenesis—a suggestion that supports the general concept of specific functions for the LC3 and GABARAP subfamilies in phagophore elongation and maturation, respectively, although species specific differences exist (Weidberg et al., 2010Weidberg H. Shvets E. Shpilka T. Shimron F. Shinder V. Elazar Z. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis.EMBO J. 2010; 29: 1792-1802Crossref PubMed Scopus (534) Google Scholar) Mitochondria are eliminated by autophagy when the demand for metabolic capacity declines, for example in yeast when they change from log-phase growth to the stationary phase (Abeliovich, 2011Abeliovich H. Stationary-phase mitophagy in respiring Saccharomyces cerevisiae.Antioxid. Redox Signal. 2011; 14: 2003-2011Crossref PubMed Scopus (12) Google Scholar) and in cone visual cells during hibernation (Remé and Young, 1977Remé C.E. Young R.W. The effects of hibernation on cone visual cells in the ground squirrel.Invest. Ophthalmol. Vis. Sci. 1977; 16: 815-840PubMed Google Scholar). Mitochondria are completely cleared by autophagy during the differentiation of specialized tissues, such as eye lens fiber cells (Costello et al., 2013Costello M.J. Brennan L.A. Basu S. Chauss D. Mohamed A. Gilliland K.O. Johnsen S. Menko A.S. Kantorow M. Autophagy and mitophagy participate in ocular lens organelle degradation.Exp. Eye Res. 2013; 116: 141-150Crossref PubMed Scopus (104) Google Scholar) and red blood cells (Heynen et al., 1985Heynen M.J. Tricot G. Verwilghen R.L. Autophagy of mitochondria in rat bone marrow erythroid cells. Relation to nuclear extrusion.Cell Tissue Res. 1985; 239: 235-239Crossref PubMed Scopus (58) Google Scholar). Another mode of mitophagy occurs in many metazoan cell types to selectively cull damaged mitochondria from the intracellular pool, apparently to help maintain quality control (Youle and van der Bliek, 2012Youle R.J. van der Bliek A.M. Mitochondrial fission, fusion, and stress.Science. 2012; 337: 1062-1065Crossref PubMed Scopus (2125) Google Scholar). The molecular mechanisms of mitophagy during the clearance of mitochondria upon reticulocyte differentiation in mammalian cells are becoming understood. The mitochondrial outer-membrane protein, NIX/BNIP3L, was found to be dramatically upregulated during reticulocyte differentiation into mature red blood cells (Aerbajinai et al., 2003Aerbajinai W. Giattina M. Lee Y.T. Raffeld M. Miller J.L. The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation.Blood. 2003; 102: 712-717Crossref PubMed Scopus (91) Google Scholar). Subsequent work revealed that circulating red blood cells in NIX knockout mice atypically retain mitochondria that are normally removed by mitophagy, establishing an important function in mitochondrial clearance for this mitochondrial membrane protein (Sandoval et al., 2008Sandoval H. Thiagarajan P. Dasgupta S.K. Schumacher A. Prchal J.T. Chen M. Wang J. Essential role for Nix in autophagic maturation of erythroid cells.Nature. 2008; 454: 232-235Crossref PubMed Scopus (873) Google Scholar, Schweers et al., 2007Schweers R.L. Zhang J. Randall M.S. Loyd M.R. Li W. Dorsey F.C. Kundu M. Opferman J.T. Cleveland J.L. Miller J.L. Ney P.A. NIX is required for programmed mitochondrial clearance during reticulocyte maturation.Proc. Natl. Acad. Sci. USA. 2007; 104: 19500-19505Crossref PubMed Scopus (684) Google Scholar). Although Nix was found to have a consensus LC3 interaction region (LIR) motif that binds to both LC3 and GABARAP (Novak et al., 2010Novak I. Kirkin V. McEwan D.G. Zhang J. Wild P. Rozenknop A. Rogov V. Löhr F. Popovic D. Occhipinti A. et al.Nix is a selective autophagy receptor for mitochondrial clearance.EMBO Rep. 2010; 11: 45-51Crossref PubMed Scopus (912) Google Scholar), suggesting it functions to recruit mitochondria into isolation membranes/phagophores, in vivo experiments indicate additional unknown functions for Nix during mitophagy more important than LIR-mediated docking to LC3 (Zhang et al., 2012Zhang J. Loyd M.R. Randall M.S. Waddell M.B. Kriwacki R.W. Ney P.A. A short linear motif in BNIP3L (NIX) mediates mitochondrial clearance in reticulocytes.Autophagy. 2012; 8: 1325-1332Crossref PubMed Scopus (60) Google Scholar). The molecular mechanisms mediating quality-control mitophagy in mammalian cells have become understood in recent years (Twig and Shirihai, 2011Twig G. Shirihai O.S. The interplay between mitochondrial dynamics and mitophagy.Antioxid. Redox Signal. 2011; 14: 1939-1951Crossref PubMed Scopus (523) Google Scholar, Youle and van der Bliek, 2012Youle R.J. van der Bliek A.M. Mitochondrial fission, fusion, and stress.Science. 2012; 337: 1062-1065Crossref PubMed Scopus (2125) Google Scholar). The mitochondrial kinase, PINK1, detects damaged mitochondria and subsequently recruits and activates the RBR E3 ubiquitin ligase, Parkin (Matsuda et al., 2010Matsuda N. Sato S. Shiba K. Okatsu K. Saisho K. Gautier C.A. Sou Y.-S. Saiki S. Kawajiri S. Sato F. et al.PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.J. Cell Biol. 2010; 189: 211-221Crossref PubMed Scopus (1342) Google Scholar, Narendra et al., 2010Narendra D.P. Jin S.M. Tanaka A. Suen D.-F. Gautier C.A. Shen J. Cookson M.R. Youle R.J. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.PLoS Biol. 2010; 8: e1000298Crossref PubMed Scopus (1992) Google Scholar). Parkin, in turn, ubiquitinates proteins on the outer mitochondrial membrane surface that likely initiate autophagosome isolation membrane encapsulation of the damaged mitochondria (Figure 2). This selective autophagy of damaged mitochondria is thought to mediate quality control (Narendra et al., 2008Narendra D. Tanaka A. Suen D.-F. Youle R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.J. Cell Biol. 2008; 183: 795-803Crossref PubMed Scopus (2856) Google Scholar). Interestingly, autosomal recessive mutations in either PINK1 or Parkin cause early onset Parkinson's disease, suggesting that insufficient mitochondrial quality control may be to blame. PINK1 is able to "sense" mitochondrial "quality" based on its turnover mechanism; PINK1 undergoes rapid and constitutive degradation in healthy mitochondria by the inner mitochondrial membrane protease PARL following import through the TOM and TIM membrane translocation complexes. When the membrane potential across the inner mitochondrial membrane that is normally generated by oxidative phosphorylation deteriorates, PINK1 import into the inner mitochondrial membrane and cleavage by PARL are blocked. PINK1 instead starts to accumulate on the outer mitochondrial membrane with its kinase domain facing the cytosol where Parkin resides (Figure 2). On the outer mitochondrial membrane PINK1 associates in a 2:1 molecular complex with the TOM import machinery (Lazarou et al., 2012Lazarou M. Jin S.M. Kane L.A. Youle R.J. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin.Dev. 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PINK1 therefore selectively accumulates only on those mitochondria within a cell population that are dysfunctional and thus flags them for elimination (Narendra et al., 2010Narendra D.P. Jin S.M. Tanaka A. Suen D.-F. Gautier C.A. Shen J. Cookson M.R. Youle R.J. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.PLoS Biol. 2010; 8: e1000298Crossref PubMed Scopus (1992) Google Scholar). The accumulation of active PINK1 on mitochondria recruits Parkin and activates its latent HECT/RING hybrid mechanism of ubiquitin transfer. The crystal structure of Parkin shows how the enzyme is held in the cytosol in an autoinhibited form (Riley et al., 2013Riley B.E. Lougheed J.C. Callaway K. Velasquez M. Brecht E. Nguyen L. Shaler T. Walker D. Yang Y. Regnstrom K. et al.Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases.Nat. Commun. 2013; 4: 1982Crossref PubMed Scopus (235) Google Scholar, Trempe et al., 2013Trempe J.-F. Sauvé V. Grenier K. Seirafi M. Tang M.Y. Ménade M. Al-Abdul-Wahid S. Krett J. Wong K. Kozlov G. et al.Structure of parkin reveals mechanisms for ubiquitin ligase activation.Science. 2013; 340: 1451-1455Crossref PubMed Scopus (367) Google Scholar, Wauer and Komander, 2013Wauer T. Komander D. Structure of the human Parkin ligase domain in an autoinhibited state.EMBO J. 2013; 32: 2099-2112Crossref PubMed Scopus (233) Google Scholar). Although the structure of active Parkin remains unknown, it appears to form a dimer or multimer upon activation. PINK1 kinase activity is required for Parkin activation, but it is not clear what the essential PINK1 substrate is. PINK1 ectopically placed on peroxisomes recruits Parkin to peroxisomes ruling out mitochondria-specific PINK1 substrates as essential intermediates of Parkin activation (Lazarou et al., 2012Lazarou M. Jin S.M. Kane L.A. Youle R.J. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin.Dev. Cell. 2012; 22: 320-333Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). Other models indicate that PINK1 autophosphorylation (Okatsu et al., 2012Okatsu K. Oka T. Iguchi M. Imamura K. Kosako H. Tani N. Kimura M. Go E. Koyano F. Funayama M. et al.PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria.Nat. Commun. 2012; 3: 1016Crossref PubMed Scopus (321) Google Scholar) or Parkin phosphorylation (Kondapalli et al., 2012Kondapalli C. Kazlauskaite A. Zhang N. Woodroof H.I. Campbell D.G. Gourlay R. Burchell L. Walden H. Macartney T.J. Deak M. et al.PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65.Open Biol. 2012; 2: 120080Crossref PubMed Scopus (621) Google Scholar) are involved or that an unknown cytosolic protein is the essential PINK1 substrate mediating Parkin translocation. Once activated, Parkin ubiquitinates scores of substrates on the mitochondria and in the cytosol (Sarraf et al., 2013Sarraf S.A. Raman M. Guarani-Pereira V. Sowa M.E. Huttlin E.L. Gygi S.P. Harper J.W. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.Nature. 2013; 496: 372-376Crossref PubMed Scopus (711) Google Scholar). Which, if any, of these individual substrates is essential for autophagy remains unknown. Ubiquitin chain linkage or ubiquitin chain density above a certain threshold may be as or more important than the identity of the ubiquitinated substrate—as discussed below in relation to the role of ubiquitin in xenophagy. Parkin appears to attach several ubiquitin chain linkages types, including K48-, K63-, and K27-linked chains, to proteins located on the outer mitochondrial surface (Chan et al., 2011Chan N.C. Salazar A.M. Pham A.H. Sweredoski M.J. Kolawa N.J. Graham R.L.J. Hess S. Chan D.C. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy.Hum. Mol. Genet. 2011; 20: 1726-1737Crossref PubMed Scopus (764) Google Scholar, Geisler et al., 2010Geisler S. Holmström K.M. Skujat D. Fiesel F.C. Rothfuss O.C. Kahle P.J. Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.Nat. Cell Biol. 2010; 12: 119-131Crossref PubMed Scopus (2030) Google Scholar, van Wijk et al., 2012van Wijk S.J.L. Fiskin E. Putyrski M. Pampaloni F. Hou J. Wild P. Kensche T. Grecco H.E. Bastiaens P. Dikic I. Fluorescence-Based Sensors to Monitor Localization and Functions of Linear and K63-Linked Ubiquitin Chains in Cells.Molecular Cell. 2012; 47: 797-809Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). The K63-linked ubiquitin chains are likely to be important for recruitment of the cargo receptor p62 (Geisler et al., 2010Geisler S. Holmström K.M. Skujat D. Fiesel F.C. Rothfuss O.C. Kahle P.J. Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.Nat. Cell Biol. 2010; 12: 119-131Crossref PubMed Scopus (2030) Google Scholar) and other adaptor proteins that can engage phagophore-bound LC3 and GABARAP via LIR motifs. The K48-linked ubiquitin chains are likely involved in the recruitment of the AAA+ ATPase p97 (Tanaka et al., 2010Tanaka A. Cleland M.M. Xu S. Narendra D.P. Suen D.-F. Karbowski M. Youle R.J. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.J. Cell Biol. 2010; 191: 1367-1380Crossref PubMed Scopus (1012) Google Scholar) and the proteasome (Chan et al., 2011Chan N.C. Salazar A.M. Pham A.H. Sweredoski M.J. Kolawa N.J. Graham R.L.J. Hess S. Chan D.C. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy.Hum. Mol. Genet. 2011; 20: 1726-1737Crossref PubMed Scopus (764) Google Scholar) to mitochondria, which respectively mediate the extraction and proteosomal degradation of ubiquitinated outer mitochondrial membrane proteins. The robust proteosomal elimination of outer mitochondrial membrane proteins appears capable of rupturing the outer membrane and may yield a membrane damage signal that triggers mitophagy and recruitment of autophagosome machinery downstream of Parkin (Yoshii et al., 2011Yoshii S.R. Kishi C. Ishihara N. Mizushima N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane.J. Biol. Chem. 2011; 286: 19630-19640Crossref PubMed Scopus (467) Google Scholar). Parkin-mediated mitophagy also involves noncanonical adaptor proteins that guide autophagic targeting of mitochondria. Notably, two RabGAPs, TBC1D15 and TBC1D17, which are bound to the outer mitochondrial membrane protein, Fis1, interact with LC3/GABARAP and participate in isolation membrane formation during Parkin-mediated mitophagy (Yamano et al., 2014Yamano K. Fogel A.I. Wang C. van der Bliek A.M. Youle R.J. Wang C. Trichet M. van der Bliek A.M. Boulogne C. Youle R.J. et al.Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy.Elife. 2014; 3: e01612Crossref Scopus (57) Google Scholar). Despite identical core LIR motifs, TBC1D15 and TBC1D17 bind differentially to LC3 and GABARAP members of the ATG8 family. Interestingly, both require their RabGAP activity in the conserved TBC domain to restrict excessive LC3 protein accumulation during mitophagy. This stems from excessive Rab7 activity in the absence of RabGAP activity that appears normally to be involved in LC3 membrane recruitment and trafficking to mitochondria during mitophagy but not during starvation-induced autophagy. Additionally, recent evidence suggests that autophagic machinery can be recruited to targeted mitochondria independent of LC3. Ulk1, Atg14, DFCP1, WIPI-1, and Atg16L1 (Itakura et al., 2012Itakura E. Kishi-Itakura C. Koyama-Honda I. Mizushima N. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy.J. Cell Sci. 2012; 125: 1488-1499Crossref PubMed Scopus (213) Google Scholar) are recruited to autophagosomes associated with Parkin-bound and ubiquitin-labeled mitochondria even in the absence of membrane bound LC3. Ulk1 and Atg9A recruitment to damaged mitochondria are downstream of Parkin activity but independent of one another. What signals the independent recruitment of autophagy machinery proteins to mitochondria-associated isolation membranes is unknown but may stem from different linkage types of ubiquitin chains. Mitochondrial fission is associated with mitophagy either to reduce the size of elongated mitochondria to facilitate engulfment by autophagosomes or to prevent damaged mitochondria from fusing with healthy mitochondria and impairing them by the exchange of damaged proteins and lipids (Twig et al., 2008Twig G. Elorza A. Molina A.J.A. Mohamed H. Wikstrom J.D. Walzer G. Stiles L. Haigh S.E. Katz S. Las G. et al.Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.EMBO J. 2008; 27: 433-446Crossref PubMed Scopus (2186) Google Scholar). Interestingly, Parkin ubiquitinates the mitochondrial fission proteins Mfn1 and Mfn2 possibly to actively prevent mitochondrial refusion in both Drosophila and mammalian cells (Gegg et al., 2010Gegg M.E. Cooper J.M. Chau K.-Y. Rojo M. Schapira A.H.V. Taanman J.-W. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy.Hum. Mol. Genet. 2010; 19: 4861-4870Crossref PubMed Scopus (685) Google Scholar, Poole et al., 2010Poole A.C. Thomas R.E. Yu S. Vincow E.S. Pallanck L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway.PLoS ONE. 2010; 5: e10054Crossref PubMed Scopus (364) Google Scholar, Tanaka et al., 2010Tanaka A. Cleland M.M. Xu S. Narendra D.P. Suen D.-F. Karbowski M. Youle R.J. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.J. Cell Biol. 2010; 191: 1367-1380Crossref PubMed Scopus (1012) Google Scholar, Ziviani et al., 2010Ziviani E. Tao R.N. Whitworth A.J. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.Proc. Natl. Acad. Sci. USA. 2010; 107: 5018-5023Crossref PubMed Scopus (591) Google Scholar). This conclusion is corroborated by genetic studies in Drosophila where promotion of mitochondrial fission compensates for loss of PINK1 and Parkin and inhibition of fission exacerbates the phenotype of PINK1 and Parkin loss (Deng et al., 2008Deng H. Dodson M.W. Huang H. Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila.Proc. Natl. Acad. Sci. USA. 2008; 105: 14503-14508Crossref PubMed Scopus (559) Google Scholar, Park et al., 2009Park J. Lee G. Chung J. The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process.Biochem. Biophys. Res. Commun. 2009; 378: 518-523Crossref PubMed Scopus (149) Google Scholar, Poole et al., 2008Poole A.C. Thomas R.E. Andrews L.A. McBride H.M. Whitworth A.J. 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