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PMID: 22743996 Published · ppublish English Journal Article Review

The pathways of mitophagy for quality control and clearance of mitochondria.

Cell death and differentiation ·Vol. 20 ·No. 1 ·2013-01-00 ·Pages 31-42

Ashrafi G, Schwarz TL

Abstract

Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.

MeSH Terms
Animals Humans Mitochondria/genetics,metabolism,physiology Mitophagy/genetics,physiology
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Ashrafi G
FM Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115, USA.
Schwarz T L
References (108)
108 references, click to expand
  1. Mitochondria supply membranes for autophagosome biogenesis during starvation.
    Cell. 2010 May 14;141(4):656-67 PMID: 20478256
  2. Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition.
    Hum Mol Genet. 2012 Mar 1;21(5):978-90 PMID: 22080835
  3. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.
    Nature. 2006 Jun 29;441(7097):1157-61 PMID: 16672980
  4. Parkin mono-ubiquitinates Bcl-2 and regulates autophagy.
    J Biol Chem. 2010 Dec 3;285(49):38214-23 PMID: 20889974
  5. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.
    J Cell Biol. 2010 Dec 27;191(7):1367-80 PMID: 21173115
  6. Parkin-mediated lysine 63-linked polyubiquitination: a link to protein inclusions formation in Parkinson's and other conformational diseases?
    Neurobiol Aging. 2006 Apr;27(4):524-9 PMID: 16213628
  7. The origin of the autophagosomal membrane.
    Nat Cell Biol. 2010 Sep;12(9):831-5 PMID: 20811355
  8. Induction of autophagy in axonal dystrophy and degeneration.
    J Neurosci. 2006 Aug 2;26(31):8057-68 PMID: 16885219
  9. Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy.
    Mol Cell. 2011 Aug 19;43(4):572-85 PMID: 21855797
  10. Uth1p is involved in the autophagic degradation of mitochondria.
    J Biol Chem. 2004 Sep 10;279(37):39068-74 PMID: 15247238
  11. Mitochondrial membrane potential in axons increases with local nerve growth factor or semaphorin signaling.
    J Neurosci. 2008 Aug 13;28(33):8306-15 PMID: 18701693
  12. Nix, a receptor protein for mitophagy in mammals.
    Autophagy. 2010 Apr;6(3):433-5 PMID: 20200478
  13. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.
    J Cell Biol. 2010 Apr 19;189(2):211-21 PMID: 20404107
  14. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation.
    Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10190-5 PMID: 21646527
  15. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.
    EMBO J. 2008 Jan 23;27(2):433-46 PMID: 18200046
  16. Mechanisms of mitophagy.
    Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14 PMID: 21179058
  17. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease.
    J Neurosci. 2008 Jul 2;28(27):6926-37 PMID: 18596167
  18. Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model.
    Aging Cell. 2008 Dec;7(6):920-3 PMID: 18691181
  19. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane.
    J Biol Chem. 2011 Jun 3;286(22):19630-40 PMID: 21454557
  20. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility.
    Cell. 2011 Nov 11;147(4):893-906 PMID: 22078885
  21. The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases.
    Biochim Biophys Acta. 2009 Sep;1793(9):1496-507 PMID: 19339210
  22. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells.
    Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11835-40 PMID: 20547844
  23. ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death.
    Cell. 2010 Aug 20;142(4):590-600 PMID: 20723759
  24. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells.
    J Cell Biol. 2009 Dec 28;187(7):959-66 PMID: 20038677
  25. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.
    J Biol Chem. 2008 Apr 18;283(16):10892-903 PMID: 18281291
  26. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease.
    Cell. 2011 Mar 4;144(5):689-702 PMID: 21376232
  27. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope.
    J Biophys Biochem Cytol. 1957 May 25;3(3):349-62 PMID: 13438920
  28. A genomic screen for yeast mutants defective in mitophagy.
    Autophagy. 2010 Feb;6(2):278-80 PMID: 20364111
  29. Mitophagy in yeast occurs through a selective mechanism.
    J Biol Chem. 2008 Nov 21;283(47):32386-93 PMID: 18818209
  30. Biophysical properties of mitochondrial fusion events in pancreatic beta-cells and cardiac cells unravel potential control mechanisms of its selectivity.
    Am J Physiol Cell Physiol. 2010 Aug;299(2):C477-87 PMID: 20445168
  31. In vivo and in vitro effects of the mitochondrial uncoupler FCCP on microtubules.
    EMBO J. 1982;1(11):1347-52 PMID: 6765194
  32. The PINK1/Parkin pathway regulates mitochondrial morphology.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43 PMID: 18230723
  33. Mitochondrial turnover in animal cells. Half-lives of mitochondria and mitochondrial subfractions of rat liver based on [14C]bicarbonate incorporation.
    J Biol Chem. 1981 Aug 25;256(16):8652-7 PMID: 7263675
  34. Lysomes in the rat sciatic nerve following crush.
    J Cell Biol. 1965 Dec;27(3):651-69 PMID: 5885432
  35. Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast.
    J Cell Biol. 2006 Dec 18;175(6):925-35 PMID: 17178909
  36. Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission.
    Science. 2011 Nov 25;334(6059):1144-7 PMID: 22033522
  37. The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth.
    J Cell Sci. 1993 Mar;104 ( Pt 3):917-27 PMID: 8314882
  38. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells.
    J Neurosci. 2011 Apr 20;31(16):5970-6 PMID: 21508222
  39. Plasma membrane contributes to the formation of pre-autophagosomal structures.
    Nat Cell Biol. 2010 Aug;12(8):747-57 PMID: 20639872
  40. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.
    Annu Rev Genet. 2005;39:359-407 PMID: 16285865
  41. Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons.
    Curr Biol. 2012 Mar 20;22(6):545-52 PMID: 22342752
  42. AAA proteases of mitochondria: quality control of membrane proteins and regulatory functions during mitochondrial biogenesis.
    Biochem Soc Trans. 2001 Aug;29(Pt 4):431-6 PMID: 11498003
  43. Autophagy: renovation of cells and tissues.
    Cell. 2011 Nov 11;147(4):728-41 PMID: 22078875
  44. The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons.
    Hum Mol Genet. 2011 Aug 15;20(16):3227-40 PMID: 21613270
  45. Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast.
    Cell Death Differ. 2005 Dec;12(12):1613-21 PMID: 15947785
  46. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.
    Nat Cell Biol. 2012 Jan 22;14(2):177-85 PMID: 22267086
  47. Normal and disordered reticulocyte maturation.
    Curr Opin Hematol. 2011 May;18(3):152-7 PMID: 21423015
  48. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent.
    J Cell Biol. 2006 May 22;173(4):545-57 PMID: 16717129
  49. Parkin interacts with Ambra1 to induce mitophagy.
    J Neurosci. 2011 Jul 13;31(28):10249-61 PMID: 21753002
  50. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy.
    J Cell Sci. 2012 Mar 15;125(Pt 6):1488-99 PMID: 22275429
  51. Mitochondria in cell death.
    Essays Biochem. 2010;47:99-114 PMID: 20533903
  52. Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos.
    Science. 2011 Nov 25;334(6059):1141-4 PMID: 21998252
  53. Parkin stabilizes PINK1 through direct interaction.
    Biochem Biophys Res Commun. 2009 Jun 5;383(3):331-5 PMID: 19358826
  54. PINK1 cleavage at position A103 by the mitochondrial protease PARL.
    Hum Mol Genet. 2011 Mar 1;20(5):867-79 PMID: 21138942
  55. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation.
    Biochem Biophys Res Commun. 2008 Dec 19;377(3):975-80 PMID: 18957282
  56. Axonal mitochondrial transport and potential are correlated.
    J Cell Sci. 2004 Jun 1;117(Pt 13):2791-804 PMID: 15150321
  57. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.
    J Cell Biol. 2010 May 17;189(4):671-9 PMID: 20457763
  58. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.
    J Cell Biol. 2008 Dec 1;183(5):795-803 PMID: 19029340
  59. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.
    Nat Cell Biol. 2010 Feb;12(2):119-31 PMID: 20098416
  60. A unified nomenclature for yeast autophagy-related genes.
    Dev Cell. 2003 Oct;5(4):539-45 PMID: 14536056
  61. Mitochondrial pathology in Parkinson's disease.
    Mt Sinai J Med. 2011 Nov-Dec;78(6):872-81 PMID: 22069211
  62. Mitophagy selectively degrades individual damaged mitochondria after photoirradiation.
    Antioxid Redox Signal. 2011 May 15;14(10):1919-28 PMID: 21126216
  63. Chaperone-mediated autophagy: molecular mechanisms and physiological relevance.
    Semin Cell Dev Biol. 2010 Sep;21(7):719-26 PMID: 20176123
  64. IF1, the endogenous regulator of the F(1)F(o)-ATPsynthase, defines mitochondrial volume fraction in HeLa cells by regulating autophagy.
    Biochim Biophys Acta. 2009 May;1787(5):393-401 PMID: 19269273
  65. NIX is required for programmed mitochondrial clearance during reticulocyte maturation.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19500-5 PMID: 18048346
  66. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes.
    Annu Rev Genet. 2005;39:503-36 PMID: 16285870
  67. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
    PLoS Biol. 2010 Jan 26;8(1):e1000298 PMID: 20126261
  68. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3064-9 PMID: 9096346
  69. Nix is a selective autophagy receptor for mitochondrial clearance.
    EMBO Rep. 2010 Jan;11(1):45-51 PMID: 20010802
  70. Selective and non-selective autophagic degradation of mitochondria in yeast.
    Autophagy. 2007 Jul-Aug;3(4):329-36 PMID: 17377488
  71. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
    Nature. 1998 Apr 9;392(6676):605-8 PMID: 9560156
  72. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy.
    Cell Death Differ. 2010 Jun;17(6):962-74 PMID: 20057503
  73. Beclin 1-independent autophagy contributes to apoptosis in cortical neurons.
    Autophagy. 2011 Oct;7(10):1115-31 PMID: 21646862
  74. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83 PMID: 12642658
  75. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway.
    PLoS One. 2010 Apr 07;5(4):e10054 PMID: 20383334
  76. Axoplasmic organelles at nodes of Ranvier. I. Occurrence and distribution in large myelinated spinal root axons of the adult cat.
    J Neurocytol. 1993 Nov;22(11):925-40 PMID: 7507975
  77. Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress: implications for neurodegeneration and cell death.
    Autophagy. 2007 Nov-Dec;3(6):663-6 PMID: 17622797
  78. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction.
    J Cell Biol. 1992 Oct;119(2):301-11 PMID: 1400575
  79. The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking.
    J Neurochem. 2011 Jun;117(5):856-67 PMID: 21426348
  80. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy.
    Hum Mol Genet. 2011 May 1;20(9):1726-37 PMID: 21296869
  81. Hereditary early-onset Parkinson's disease caused by mutations in PINK1.
    Science. 2004 May 21;304(5674):1158-60 PMID: 15087508
  82. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes.
    Curr Biol. 2012 Jan 24;22(2):135-41 PMID: 22226745
  83. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin.
    Dev Cell. 2012 Feb 14;22(2):320-33 PMID: 22280891
  84. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy.
    Autophagy. 2009 Jul;5(5):690-8 PMID: 19363302
  85. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming.
    J Biol Chem. 2010 Sep 3;285(36):27879-90 PMID: 20573959
  86. A genomic screen for yeast mutants defective in selective mitochondria autophagy.
    Mol Biol Cell. 2009 Nov;20(22):4730-8 PMID: 19793921
  87. Autophagy receptors in developmental clearance of mitochondria.
    Autophagy. 2011 Mar;7(3):301-3 PMID: 21206218
  88. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both.
    Autophagy. 2010 Nov;6(8):1090-106 PMID: 20890124
  89. Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging.
    Neurobiol Dis. 2011 Jul;43(1):46-51 PMID: 20887789
  90. The machines that divide and fuse mitochondria.
    Annu Rev Biochem. 2007;76:751-80 PMID: 17362197
  91. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons.
    J Cell Biol. 2012 Feb 20;196(4):407-17 PMID: 22331844
  92. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission.
    J Biol Chem. 2009 May 15;284(20):13843-13855 PMID: 19279012
  93. Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation.
    Curr Opin Cell Biol. 2011 Aug;23(4):476-82 PMID: 21705204
  94. Image-based genome-wide siRNA screen identifies selective autophagy factors.
    Nature. 2011 Dec 1;480(7375):113-7 PMID: 22020285
  95. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment.
    EMBO Rep. 2012 Apr;13(4):378-85 PMID: 22354088
  96. Parkinson's disease: a rethink of rodent models.
    Exp Brain Res. 2006 Aug;173(2):196-204 PMID: 16639500
  97. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.
    Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23 PMID: 20194754
  98. Autophagy basics.
    Microbiol Immunol. 2011 Jan;55(1):1-11 PMID: 21175768
  99. Atg32 is a mitochondrial protein that confers selectivity during mitophagy.
    Dev Cell. 2009 Jul;17(1):98-109 PMID: 19619495
  100. Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization.
    Hum Mol Genet. 2011 Mar 1;20(5):927-40 PMID: 21147754
  101. Necrotic cell death: From reversible mitochondrial uncoupling to irreversible lysosomal permeabilization.
    Exp Cell Res. 2009 Jan 1;315(1):26-38 PMID: 18951891
  102. Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy.
    Cell Death Differ. 2007 Sep;14(9):1647-56 PMID: 17541427
  103. Essential role for Nix in autophagic maturation of erythroid cells.
    Nature. 2008 Jul 10;454(7201):232-5 PMID: 18454133
  104. Ambra1: a Parkin-binding protein involved in mitophagy.
    Autophagy. 2011 Dec;7(12):1555-6 PMID: 21921694
  105. The interplay between mitochondrial dynamics and mitophagy.
    Antioxid Redox Signal. 2011 May 15;14(10):1939-51 PMID: 21128700
  106. Oxidative phosphorylation at the fin de siècle.
    Science. 1999 Mar 5;283(5407):1488-93 PMID: 10066163
  107. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy.
    Dev Cell. 2009 Jul;17(1):87-97 PMID: 19619494
  108. Mitophagy in cells with mtDNA mutations: being sick is not enough.
    Autophagy. 2012 Apr;8(4):699-700 PMID: 22361618
Article Info
Journal
Cell death and differentiation
Abbr.
Cell Death Differ
ISSN
1476-5403
DOI
10.1038/cdd.2012.81
Published
2013-01-00
Epub
2012-00-29
Pages
31-42
Language
English
Region
England
NLM ID
9437445
PMCID
PMC3524633
Subset
IM
Grants
NICHD NIH HHS · P30 HD018655 · United States
External Links
PubMed source DOI: 10.1038/cdd.2012.81 PMC Full Text View journal details
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