Skip to main content

Advertisement

SpringerLink
Log in

Roles of mitophagy in cellular physiology and development

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

The autophagic degradation of mitochondria, or mitophagy, has been shown to occur in eukaryotic cells under various physiological conditions. Broadly, these fall into two categories: quality-control related mitophagy and developmentally induced mitophagy. Quality-control related mitophagy, which is the lysosomal/vacuolar degradation of malfunctioning or superfluous mitochondria, is an important housekeeping function in respiring eukaryotic cells. It plays an essential role in physiological homeostasis and its deregulation has been linked to the progression of late-onset diseases. On the other hand, developmental processes such as reticulocyte maturation have also been shown to involve mitophagy. Importantly, there are clear differences between these processes. Unlike our knowledge of the more general degradation of soluble cytosolic content during starvation-induced macroautophagy, the mechanisms involved in the selective autophagic degradation of mitochondria have only recently begun to receive significant attention. Here, we review the current literature on these topics and proceed to provide specific examples from yeast and mammalian systems. Finally, we cover experimental approaches, with a focus on proteomic methods dedicated to the study of mitophagy in different systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abeliovich H (2011) Stationary-phase mitophagy in respiring Saccharomyces cerevisiae. Antioxid Redox Signal 14:2003–2011

    Article  CAS  PubMed  Google Scholar 

  • Abeliovich H, Dunn WA, Kim J, Klionsky DJ (2000) Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. J Cell Biol 151:1025–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abeliovich H, Zarei M, Rigbolt KT, Youle RJ, Dengjel J (2013) Involvement of mitochondrial dynamics in the segregation of mitochondrial matrix proteins during stationary phase mitophagy. Nat Commun 4:2789

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Abeliovich H, Zhang C, Dunn WA, Shokat KM, Klionsky DJ (2003) Chemical genetic analysis of Apg1 reveals a non-kinase role in the induction of autophagy. Mol Biol Cell 14:477–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahlqvist KJ, Leoncini S, Pecorelli A, Wortmann SB, Ahola S, Forsström S, Guerranti R, De Felice C, Smeitink J, Ciccoli L, Hämäläinen RH, Suomalainen A (2015) MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction. Nat Commun 6:6494

  • Alers S, Löffler AS, Paasch F, Dieterle AM, Keppeler H, Lauber K, Campbell DG, Fehrenbacher B, Schaller M, Wesselborg S, Stork B (2011) Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction. Autophagy 7:1423–1433

    Article  PubMed  CAS  Google Scholar 

  • Aoki Y, Kanki T, Hirota Y, Kurihara Y, Saigusa T, Uchiumi T, Kang D (2011) Phosphorylation of Ser114 on Atg32 mediates mitophagy. Mol Biol Cell 22:3206–3217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

  • Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466:68–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29:2570–2581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Böckler S, Westermann B (2014) Mitochondrial ER contacts are crucial for mitophagy in yeast. Dev Cell 28:450–458

  • Budovskaya YV, Stephan JS, Reggiori F, Klionsky DJ, Herman PK (2004) The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. J Biol Chem 279:20663–20671

  • Busch KB, Kowald A, Spelbrink JN (2014) Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity. Philos Trans R Soc Lond B 369:20130442

    Article  CAS  Google Scholar 

  • Chan EY, Longatti A, McKnight NC, Tooze SA (2009) Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 29:157–171

    Article  CAS  PubMed  Google Scholar 

  • Chauhan S, Mandell MA, Deretic V (2015) IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol Cell 58:507–521

  • Chen Y, Dorn GW (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheong H, Lindsten T, Wu J, Lu C, Thompson CB (2011) Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci U S A 108:11121–11126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuervo AM (2008) Autophagy and aging: keeping that old broom working. Trends Genet 24:604–612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cui J, Bai XY, Shi S, Cui S, Hong Q, Cai G, Chen X (2012) Age-related changes in the function of autophagy in rat kidneys. Age (Dordr) 34:329–339

    Article  CAS  Google Scholar 

  • Deffieu M, Bhatia-Kissova 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

  • Dengjel J, Abeliovich H (2014) Musical chairs during mitophagy. Autophagy 10:706–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deter RL, Baudhuin P, De Duve C (1967) Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol 35:C11–C16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diot A, Hinks-Roberts A, Lodge T, Liao C, Dombi E, Morten K, Brady S, Fratter C, Carver J, Muir R, Davis R, Green CJ, Johnston I, Hilton-Jones D, Sue C, Mortiboys H, Poulton J (2015) A novel quantitative assay of mitophagy: Combining high content fluorescence microscopy and mitochondrial DNA load to quantify mitophagy and identify novel pharmacological tools against pathogenic heteroplasmic mtDNA. Pharmacol Res 100:24–35

    Article  CAS  PubMed  Google Scholar 

  • Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461

  • Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24:24–41

    Article  CAS  PubMed  Google Scholar 

  • Foster LJ, de Hoog CL, Zhang Y, Zhang Y, Xie X, Mootha VK, Mann M (2006) A mammalian organelle map by protein correlation profiling. Cell 125:187–199

    Article  CAS  PubMed  Google Scholar 

  • Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362

  • Gong G, Song M, Csordas G, Kelly DP, Matkovich SJ, Dorn GW (2015) Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350:aad2459

  • Gordon PB, Seglen PO (1988) Prelysosomal convergence of autophagic and endocytic pathways. Biochem Biophys Res Commun 151:40–47

    Article  CAS  PubMed  Google Scholar 

  • Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–653

    Article  CAS  PubMed  Google Scholar 

  • Greenamyre JT, MacKenzie G, Peng TI, Stephans SE (1999) Mitochondrial dysfunction in Parkinson’s disease. Biochem Soc Symp 66:85–97

  • Hämäläinen RH, Manninen T, Koivumäki H, Kislin M, Otonkoski T, Suomalainen A (2013) Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A > G mutation in human induced pluripotent stem cell-derived disease model. Proc Natl Acad Sci U S A 110:E3622–E3630

    Article  PubMed  PubMed Central  Google Scholar 

  • Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y (2007) The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282:37298–37302

  • Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N (2008) FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181:497–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harding TM, Morano KA, Scott SV, Klionsky DJ (1995) Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol 131:591–602

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

  • Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW (2015) The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy. Mol Cell 60:7–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N (2009a) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N (2009b) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5:973–979

    Article  CAS  PubMed  Google Scholar 

  • Hung YH, Chen LM, Yang JY, Yang WY (2013) Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat Commun 4:2111

    Article  PubMed  CAS  Google Scholar 

  • Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y (2000) A ubiquitin-like system mediates protein lipidation. Nature 408:488–492

  • Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191:933–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Journo D, Mor A, Abeliovich H (2009) Aup1-mediated regulation of Rtg3 during mitophagy. J Biol Chem 284:35885–35895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y (2005) Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 16:2544–2553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150:1507–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamber RA, Shoemaker CJ, Denic V (2015) Receptor-Bound Targets of Selective Autophagy Use a Scaffold Protein to Activate the Atg1 Kinase. Mol Cell 59:372–381

    Article  CAS  PubMed  Google Scholar 

  • Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205:143–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ (2009) Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell 17:98–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanki T, Wang K, Klionsky DJ (2010) A genomic screen for yeast mutants defective in mitophagy. Autophagy 6:278–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM (2014) Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J 460:127–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khaminets A, Heinrich T, Mari M, Grumati P, Huebner AK, Akutsu M, Liebmann L, Stolz A, Nietzsche S, Koch N, Mauthe M, Katona I, Qualmann B, Weis J, Reggiori F, Kurth I, Hübner CA, Dikic I (2015) Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522:354–358

  • Kim TY, Wang D, Kim AK, Lau E, Lin AJ, Liem DA, Zhang J, Zong NC, Lam MP, Ping P (2012) Metabolic labeling reveals proteome dynamics of mouse mitochondria. Mol Cell Proteomics 11:1586–1594

  • Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, Noda T, Ohsumi Y (1999) Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 147:435–446

  • Kissova I, Deffieu M, Manon S, Camougrand N (2004) Uth1p is involved in the autophagic degradation of mitochondria. J Biol Chem 279:39068–39074

    Article  CAS  PubMed  Google Scholar 

  • Klionsky DJ, Cueva R, Yaver DS (1992) Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway. J Cell Biol 119:287–299

    Article  CAS  PubMed  Google Scholar 

  • Köfinger J, Ragusa MJ, Lee IH, Hummer G, Hurley JH (2015) Solution structure of the Atg1 complex: implications for the architecture of the phagophore assembly site. Structure 23:809–818

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H, Macartney TJ, Deak M, Knebel A, Alessi DR, Muqit MM (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2:120080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koopmann R, Muhammad K, Perbandt M, Betzel C, Duszenko M (2009) Trypanosoma brucei ATG8: structural insights into autophagic-like mechanisms in protozoa. Autophagy 5:1085–1091

    Article  CAS  PubMed  Google Scholar 

  • Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510:162–166

    CAS  PubMed  Google Scholar 

  • Kraft C, Peter M (2008) Is the Rsp5 ubiquitin ligase involved in the regulation of ribophagy. Autophagy 4:838–840

    Article  CAS  PubMed  Google Scholar 

  • Ktistakis NT, Tooze SA (2016) Digesting the expanding mechanisms of autophagy. Trends Cell Biol (in press)

  • Kuma A, Mizushima N, Ishihara N, Ohsumi Y (2002) Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J Biol Chem 277:18619–18625

  • Kumaran R, Cookson MR (2015) Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson’s disease. Hum Mol Genet 24:R32–44

  • Lam SS, Martell JD, Kamer KJ, Deerinck TJ, Ellisman MH, Mootha VK, Ting AY (2015) Directed evolution of APEX2 for electron microscopy and proximity labeling. Nat Methods 12:51–54

    Article  CAS  PubMed  Google Scholar 

  • Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin MG, Hurley JH (2016) Structure and function of the ULK1 complex in autophagy. Curr Opin Cell Biol 39:61–68

  • Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan J (2010) Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A 107:14164–14169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, Chen Q (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 14:177–185

    Article  PubMed  CAS  Google Scholar 

  • Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC (2014) Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509:105–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao K, Wang K, Liu X, Klionsky DJ (2013) The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Dev Cell 26:9–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mari M, Griffith J, Rieter E, Krishnappa L, Klionsky DJ, Reggiori F (2010) An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J Cell Biol 190:1005–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuura A, Tsukada M, Wada Y, Ohsumi Y (1997) Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192:245–250

  • Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK (2011) The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 117:856–867

  • Mercer CA, Kaliappan A, Dennis PB (2009) A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 5:649–662

    Article  CAS  PubMed  Google Scholar 

  • Mijaljica D, Devenish RJ (2013) Nucleophagy at a glance. J Cell Sci 126:4325–4330

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y (1998) A protein conjugation system essential for autophagy. Nature 395:395–398

  • Mochida K, Oikawa Y, Kimura Y, Kirisako H, Hirano H, Ohsumi Y, Nakatogawa H (2015) Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature 522:359–362

    Article  CAS  PubMed  Google Scholar 

  • Mootha VK, Bunkenborg J, Olsen JV, Hjerrild M, Wisniewski JR, Stahl E, Bolouri MS, Ray HN, Sihag S, Kamal M, Patterson N, Lander ES, Mann M (2003) Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115:629–640

    Article  CAS  PubMed  Google Scholar 

  • Nakatogawa H, Ichimura Y, Ohsumi Y (2007) Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130:165–178

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Noda NN, Satoo K, Fujioka Y, Kumeta H, Ogura K, Nakatogawa H, Ohsumi Y, Inagaki F (2011) Structural basis of Atg8 activation by a homodimeric E1, Atg7. Mol Cell 44:462–475

    Article  CAS  PubMed  Google Scholar 

  • Noda T, Matsuura A, Wada Y, Ohsumi Y (1995) Novel system for monitoring autophagy in the yeast Saccharomyces cerevisiae. Biochem Biophys Res Commun 210:126–132

    Article  CAS  PubMed  Google Scholar 

  • Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Löhr F, Popovic D, Occhipinti A, Reichert AS, Terzic J, Dötsch V, Ney PA, Dikic I (2010) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11:45–51

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO, Olszewski JL, Koerber JT, Xie T, Beausoleil SA, Wells JA, Gygi SP, Schulman BA, Harper JW (2014) Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 56:360–375

  • Okamoto K, Kondo-Okamoto N, Ohsumi Y (2009) Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell 17:87–97

    Article  CAS  PubMed  Google Scholar 

  • Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M (2002) Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 1:376–386

    Article  CAS  PubMed  Google Scholar 

  • Orsi A, Razi M, Dooley HC, Robinson D, Weston AE, Collinson LM, Tooze SA (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23:1860–1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Øverbye A, Fengsrud M, Seglen PO (2007) Proteomic analysis of membrane-associated proteins from rat liver autophagosomes. Autophagy 3:300–322

    Article  PubMed  Google Scholar 

  • Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papinski D, Kraft C (2014) Atg1 kinase organizes autophagosome formation by phosphorylating Atg9. Autophagy 10:1338–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papinski D, Schuschnig M, Reiter W, Wilhelm L, Barnes CA, Maiolica A, Hansmann I, Pfaffenwimmer T, Kijanska M, Stoffel I, Lee SS, Brezovich A, Lou JH, Turk BE, Aebersold R, Ammerer G, Peter M, Kraft C (2014) Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Mol Cell 53:471–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paz Y, Elazar Z, Fass D (2000) Structure of GATE-16, membrane transport modulator and mammalian ortholog of autophagocytosis factor Aut7p. J Biol Chem 275:25445–25450

    Article  CAS  PubMed  Google Scholar 

  • Petrungaro C, Zimmermann KM, Küttner V, Fischer M, Dengjel J, Bogeski I, Riemer J (2015) The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake. Cell Metab 22:721–733

    Article  CAS  PubMed  Google Scholar 

  • Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP, Hoekstra JG, Harper JW, Youle RJ (2015) Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress. Neuron 87:371–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pickrell AM, Youle RJ (2013) Mitochondrial disease: mtDNA and protein segregation mysteries in iPSCs. Curr Biol 23:R1052–R1054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polson HE, de Lartigue J, Rigden DJ, Reedijk M, Urbé S, Clague MJ, Tooze SA (2010) Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6:506–522

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Proikas-Cezanne T, Waddell S, Gaugel A, Frickey T, Lupas A, Nordheim A (2004) WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23:9314–9325

  • Radoshevich L, Murrow L, Chen N, Fernandez E, Roy S, Fung C, Debnath J (2010) ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell 142:590–600

  • Ragusa MJ, Stanley RE, Hurley JH (2012) Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis. Cell 151:1501–1512

  • Rao Y, Perna MG, Hofmann B, Beier V, Wollert T (2016) The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy. Nat Commun 7:10338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rees JS, Li XW, Perrett S, Lilley KS, Jackson AP (2015) Protein Neighbors and Proximity Proteomics. Mol Cell Proteomics 14:2848–2856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reinders J, Wagner K, Zahedi RP, Stojanovski D, Eyrich B, van der Laan M, Rehling P, Sickmann A, Pfanner N, Meisinger C (2007) Profiling phosphoproteins of yeast mitochondria reveals a role of phosphorylation in assembly of the ATP synthase. Mol Cell Proteomics 6:1896–1906

    Article  CAS  PubMed  Google Scholar 

  • Rhee HW, Zou P, Udeshi ND, Martell JD, Mootha VK, Carr SA, Ting AY (2013) Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science 339:1328–1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I (2016) Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1523926113

    Google Scholar 

  • Rodriguez-Enriquez S, He L, Lemasters JJ (2004) Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol 36:2463–2472

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Enriquez S, Kai Y, Maldonado E, Currin RT, Lemasters JJ (2009) Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes. Autophagy 5:1099–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Enriquez S, Kim I, Currin RT, Lemasters JJ (2006) Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2:39–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S (2009) Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A 106:20842–20846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakakibara K, Eiyama A, Suzuki SW, Sakoh-Nakatogawa M, Okumura N, Tani M, Hashimoto A, Nagumo S, Kondo-Okamoto N, Kondo-Kakuta C, Asai E, Kirisako H, Nakatogawa H, Kuge O, Takao T, Ohsumi Y, Okamoto K (2015) Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling. EMBO J 34:2703–2719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saksena S, Sun J, Chu T, Emr SD (2007) ESCRTing proteins in the endocytic pathway. Trends Biochem Sci 32:561–573

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Wandelmer J, Reggiori F (2013) Amphisomes: out of the autophagosome shadow. EMBO J 32:3116–3118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schneider JL, Cuervo AM (2014) Autophagy and human disease: emerging themes. Curr Opin Genet Dev 26:16–23

    Article  CAS  PubMed  Google Scholar 

  • Scott CC, Vacca F, Gruenberg J (2014) Endosome maturation, transport and functions. Semin Cell Dev Biol 31:2–10

    Article  CAS  PubMed  Google Scholar 

  • Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, Hattori N (2012) PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep 2:1002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shintani T, Huang WP, Stromhaug PE, Klionsky DJ (2002) Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. Dev Cell 3:825–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shpilka T, Weidberg H, Pietrokovski S, Elazar Z (2011) Atg8: an autophagy-related ubiquitin-like protein family. Genome Biol 12:226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sickmann A, Reinders J, Wagner Y, Joppich C, Zahedi R, Meyer HE, Schönfisch B, Perschil I, Chacinska A, Guiard B, Rehling P, Pfanner N, Meisinger C (2003) The proteome of Saccharomyces cerevisiae mitochondria. Proc Natl Acad Sci U S A 100:13207–13212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simonsen A, Wurmser AE, Emr SD, Stenmark H (2001) The role of phosphoinositides in membrane transport. Curr Opin Cell Biol 13:485–492

    Article  CAS  PubMed  Google Scholar 

  • Sin J, Andres AM, Taylor DJ, Weston T, Hiraumi Y, Stotland A, Kim BJ, Huang C, Doran KS, Gottlieb RA (2016) Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts. Autophagy 12:369–380

    Article  CAS  PubMed  Google Scholar 

  • Singh SB, Davis AS, Taylor GA, Deretic V (2006) Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313:1438–1441

  • Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soulard A, Cremonesi A, Moes S, Schütz F, Jenö P, Hall MN (2010) The rapamycin-sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. Mol Biol Cell 21:3475–3486

  • Stack JH, Horazdovsky B, Emr SD (1995) Receptor-mediated protein sorting to the vacuole in yeast: roles for a protein kinase, a lipid kinase and GTP-binding proteins. Annu Rev Cell Dev Biol 11:1–33

    Article  CAS  PubMed  Google Scholar 

  • Stolz A, Ernst A, Dikic I (2014) Cargo recognition and trafficking in selective autophagy. Nat Cell Biol 16:495–501

    Article  CAS  PubMed  Google Scholar 

  • Suen DF, Narendra DP, Tanaka A, Manfredi G, Youle RJ (2010) Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc Natl Acad Sci U S A 107:11835–11840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawara K, Suzuki NN, Fujioka Y, Mizushima N, Ohsumi Y, Inagaki F (2004) The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8. Genes Cells 9:611–618

    Article  CAS  PubMed  Google Scholar 

  • Suzuki SW, Yamamoto H, Oikawa Y, Kondo-Kakuta C, Kimura Y, Hirano H, Ohsumi Y (2015) Atg13 HORMA domain recruits Atg9 vesicles during autophagosome formation. Proc Natl Acad Sci U S A 112:3350–3355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tabata K, Matsunaga K, Sakane A, Sasaki T, Noda T, Yoshimori T (2010) Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Mol Biol Cell 21:4162–4172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M, Wolf DH (1994) Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 349:275–280

  • Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F (2009) The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10:1215–1221

    Article  CAS  PubMed  Google Scholar 

  • Tsukada M, Ohsumi Y (1993) Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333:169–174

    Article  CAS  PubMed  Google Scholar 

  • Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vittorini S, Paradiso C, Donati A, Cavallini G, Masini M, Gori Z, Pollera M, Bergamini E (1999) The age-related accumulation of protein carbonyl in rat liver correlates with the age-related decline in liver proteolytic activities. J Gerontol A 54:B318–B323

    Article  CAS  Google Scholar 

  • Vögtle FN, Burkhart JM, Rao S, Gerbeth C, Hinrichs J, Martinou JC, Chacinska A, Sickmann A, Zahedi RP, Meisinger C (2012) Intermembrane space proteome of yeast mitochondria. Mol Cell Proteomics 11:1840–1852

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488

  • Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallace DC (2010) Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 51:440–450

    CAS  PubMed  Google Scholar 

  • Wallace DC, Chalkia D (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol 5:a021220

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang T, Hay JC (2015) Alpha-synuclein toxicity in the early secretory pathway: how it drives neurodegeneration in Parkinsons Disease. Front Neurosci 9:433

  • Wang K, Jin M, Liu X, Klionsky DJ (2013) Proteolytic processing of Atg32 by the mitochondrial i-AAA protease Yme1 regulates mitophagy. Autophagy 9:1828–1836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dötsch V, Bumann D, Dikic I (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilkens V, Kohl W, Busch K (2013) Restricted diffusion of OXPHOS complexes in dynamic mitochondria delays their exchange between cristae and engenders a transitory mosaic distribution. J Cell Sci 126:103–116

    Article  CAS  PubMed  Google Scholar 

  • Wong E, Bejarano E, Rakshit M, Lee K, Hanson HH, Zaarur N, Phillips GR, Sherman MY, Cuervo AM (2012) Molecular determinants of selective clearance of protein inclusions by autophagy. Nat Commun 3:1240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME, Oeljeklaus S, Varabyova A, Lirski M, Chroscicki P, Mroczek S, Januszewicz E, Dziembowski A, Koblowska M, Warscheid B, Chacinska A (2015) Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524:485–488

    Article  CAS  PubMed  Google Scholar 

  • Xie Z, Nair U, Klionsky DJ (2008) Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell 19:3290–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto H, Kakuta S, Watanabe TM, Kitamura A, Sekito T, Kondo-Kakuta C, Ichikawa R, Kinjo M, Ohsumi Y (2012) Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J Cell Biol 198:219–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamano K, Youle RJ (2013) PINK1 is degraded through the N-end rule pathway. Autophagy 9:1758–1769

  • Yorimitsu T, Zaman S, Broach JR, Klionsky DJ. (2007) Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 18:4180–4189

  • Young AR, Chan EY, Hu XW, Köchl R, Crawshaw SG, High S, Hailey DW, Lippincott-Schwartz J, Tooze SA (2006) Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119:3888–3900

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci U S A 107:5018–5023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziviani E, Whitworth AJ (2010) How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 6:660–662

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratories is funded by Israel Science Foundation grant 422/12, the German-Israel Research Foundation (GIF) grant 1297 and the Swiss National Science Foundation, grant 31003A-166482/1. Both authors are supported by the Freiburg Institute for Advanced Studies.

Author information

Authors and Affiliations

  1. Department of Dermatology, Medical Center, Freiburg Institute for Advanced Studies (FRIAS), ZBSA Center for Biological Systems Analysis, University of Freiburg, Habsburgerstr. 49, 79104, Freiburg, Germany

    Jörn Dengjel

  2. Department of Biology, University of Fribourg, Chemin du Musée 10, 1700, Fribourg, Switzerland

    Jörn Dengjel

  3. Department of Biochemistry and Food Science, Hebrew University of Jerusalem, Rehovot, 76100, Israel

    Hagai Abeliovich

  4. FRIAS Senior Fellow and Marie Curie Fellow of the European Union Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Albertstr. 19, 79104, Freiburg, Germany

    Hagai Abeliovich

Authors
  1. Jörn Dengjel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hagai Abeliovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hagai Abeliovich.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dengjel, J., Abeliovich, H. Roles of mitophagy in cellular physiology and development. Cell Tissue Res 367, 95–109 (2017). https://doi.org/10.1007/s00441-016-2472-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2472-0

Keywords

Search

Navigation