Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Parkin and mitophagy in cancer

Oncogene volume 36, pages 1315–1327 (2017)Cite this article

Subjects

Abstract

Mitophagy, the selective engulfment and clearance of mitochondria, is essential for the homeostasis of a healthy network of functioning mitochondria and prevents excessive production of cytotoxic reactive oxygen species from damaged mitochondria. The mitochondrially targeted PTEN-induced kinase-1 (PINK1) and the E3 ubiquitin ligase Parkin are well-established synergistic mediators of the mitophagy of dysfunctional mitochondria. This pathway relies on the ubiquitination of a number of mitochondrial outer membrane substrates and subsequent docking of autophagy receptor proteins to selectively clear mitochondria. There are also alternate Parkin-independent mitophagy pathways mediated by BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 and Nip-3 like protein X as well as other effectors. There is increasing evidence that ablation of mitophagy accelerates a number of pathologies. Familial Parkinsonism is associated with loss-of-function mutations in PINK1 and Parkin. A growing number of studies have observed a correlation between impaired Parkin activity and enhanced cancer development, leading to the emerging concept that Parkin activity, or mitophagy in general, is a tumour suppression mechanism. This review examines the molecular mechanisms of mitophagy and highlights the potential links between Parkin and the hallmarks of cancer that may influence tumour development and progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Langston JW, Ballard P, Tetrud JW, Irwin I . Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 219: 979–980.

    CAS  PubMed  Google Scholar 

  2. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD . Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1989; 1: 1269.

    CAS  PubMed  Google Scholar 

  3. Cleeter MW, Cooper JM, Schapira AH . Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. J Neurochem 1992; 58: 786–789.

    CAS  PubMed  Google Scholar 

  4. Sershen H, Mason MF, Hashim A, Lajtha A . Effect of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on age-related changes in dopamine turnover and transporter function in the mouse striatum. Eur J Pharmacol 1985; 113: 135–136.

    CAS  PubMed  Google Scholar 

  5. Wagner GC, Jarvis MF, Carelli RM . Ascorbic acid reduces the dopamine depletion induced by MPTP. Neuropharmacology 1985; 24: 1261–1262.

    CAS  PubMed  Google Scholar 

  6. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392: 605–608.

    CAS  PubMed  Google Scholar 

  7. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004; 304: 1158–1160.

    CAS  PubMed  Google Scholar 

  8. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003; 299: 256–259.

    CAS  PubMed  Google Scholar 

  9. Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C et al. Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Investig 2009; 119: 650–660.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Moore DJ, Zhang L, Troncoso J, Lee MK, Hattori N, Mizuno Y et al. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum Mol Genet 2005; 14: 71–84.

    CAS  PubMed  Google Scholar 

  11. Lucking CB, Abbas N, Durr A, Bonifati V, Bonnet AM, de Broucker T et al. Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group. Lancet 1998; 352: 1355–1356.

    CAS  PubMed  Google Scholar 

  12. Hattori N, Kitada T, Matsumine H, Asakawa S, Yamamura Y, Yoshino H et al. Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Ann Neurol 1998; 44: 935–941.

    CAS  PubMed  Google Scholar 

  13. Valente EM, Bentivoglio AR, Dixon PH, Ferraris A, Ialongo T, Frontali M et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35–1p36. Am J Hum Genet 2001; 68: 895–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hatano Y, Sato K, Elibol B, Yoshino H, Yamamura Y, Bonifati V et al. PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations. Neurology 2004; 63: 1482–1485.

    CAS  PubMed  Google Scholar 

  15. Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 2004; 56: 424–427.

    CAS  PubMed  Google Scholar 

  16. Kim SY, Seong MW, Jeon BS, Kim SY, Ko HS, Kim JY et al. Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease. Clin Genet 2012; 82: 77–82.

    CAS  PubMed  Google Scholar 

  17. Kay DM, Stevens CF, Hamza TH, Montimurro JS, Zabetian CP, Factor SA et al. A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2. Neurology 2010; 75: 1189–1194.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Foroud T, Uniacke SK, Liu L, Pankratz N, Rudolph A, Halter C et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003; 60: 796–801.

    CAS  PubMed  Google Scholar 

  19. Hedrich K, Hagenah J, Djarmati A, Hiller A, Lohnau T, Lasek K et al. Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol 2006; 63: 833–838.

    PubMed  Google Scholar 

  20. Perez FA, Palmiter RD . Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA 2005; 102: 2174–2179.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP, Hoekstra JG et al. Endogenous parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 2015; 87: 371–381.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y et al. Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 2008; 27: 6002–6011.

    CAS  PubMed  Google Scholar 

  23. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci USA 2011; 108: 16259–16264.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Inzelberg R, Jankovic J . Are Parkinson disease patients protected from some but not all cancers? Neurology 2007; 69: 1542–1550.

    PubMed  Google Scholar 

  25. Xu L, Lin DC, Yin D, Koeffler HP . An emerging role of PARK2 in cancer. J Mol Med 2014; 92: 31–42.

    CAS  PubMed  Google Scholar 

  26. Saito S, Sirahama S, Matsushima M, Suzuki M, Sagae S, Kudo R et al. Definition of a commonly deleted region in ovarian cancers to a 300- kb segment of chromosome 6q27. Cancer Res 1996; 56: 5586–5589.

    CAS  PubMed  Google Scholar 

  27. Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–6q27. Proc Natl Acad Sci USA 2003; 100: 5956–5961.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Denison SR, Wang F, Becker NA, Schule B, Kock N, Phillips LA et al. Alterations in the common fragile site gene Parkin in ovarian and other cancers. Oncogene 2003; 22: 8370–8378.

    CAS  PubMed  Google Scholar 

  29. Denison SR, Callahan G, Becker NA, Phillips LA, Smith DI . Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosom Cancer 2003; 38: 40–52.

    CAS  PubMed  Google Scholar 

  30. Kong FM, Anscher MS, Washington MK, Killian JK, Jirtle RL . M6P/IGF2R is mutated in squamous cell carcinoma of the lung. Oncogene 2000; 19: 1572–1578.

    CAS  PubMed  Google Scholar 

  31. Picchio MC, Martin ES, Cesari R, Calin GA, Yendamuri S, Kuroki T et al. Alterations of the tumor suppressor gene Parkin in non-small cell lung cancer. Clin Cancer Res 2004; 10: 2720–2724.

    CAS  PubMed  Google Scholar 

  32. Olsen JH, Friis S, Frederiksen K, McLaughlin JK, Mellemkjaer L, Moller H . Atypical cancer pattern in patients with Parkinson's disease. Br J Cancer 2005; 92: 201–205.

    CAS  PubMed  Google Scholar 

  33. Watson RO, Manzanillo PS, Cox JS . Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 2012; 150: 803–815.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bento CF, Empadinhas N, Mendes V . Autophagy in the fight against tuberculosis. DNA Cell Biol 2015; 34: 228–242.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 2013; 501: 512–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lazarou M . Keeping the immune system in check: a role for mitophagy. Immunol Cell Biol 2015; 93: 3–10.

    CAS  PubMed  Google Scholar 

  37. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 2015; 524: 309–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci USA 2016; 113: 4039–4044.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gong G, Song M, Csordas G, Kelly DP, Matkovich SJ, Dorn GW 2nd . Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 2015; 350: aad2459.

    PubMed  PubMed Central  Google Scholar 

  41. Durcan TM, Fon EA . The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev 2015; 29: 989–999.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pickrell AM, Youle RJ . The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron 2015; 85: 257–273.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Trempe JF, Fon EA . Structure and function of Parkin, PINK1, and DJ-1, the three musketeers of neuroprotection. Front Neurol 2013; 4: 38.

    PubMed  PubMed Central  Google Scholar 

  44. Scarffe LA, Stevens DA, Dawson VL, Dawson TM . Parkin and PINK1: much more than mitophagy. Trends Neurosci 2014; 37: 315–324.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  46. Deas E, Plun-Favreau H, Gandhi S, Desmond H, Kjaer S, Loh SH et al. PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 2011; 20: 867–879.

    CAS  PubMed  Google Scholar 

  47. Whitworth AJ, Lee JR, Ho VM, Flick R, Chowdhury R, McQuibban GA . Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin. Dis Models Mech 2008; 1: 168–174 discussion 173.

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 2010; 107: 378–383.

    CAS  PubMed  Google Scholar 

  51. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010; 189: 211–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010; 8: e1000298.

    PubMed  PubMed Central  Google Scholar 

  53. Jin SM, Youle RJ . The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autphagy 2013; 9: 1750–1757.

    CAS  Google Scholar 

  54. Lazarou M, Jin SM, Kane LA, Youle RJ . 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: 320–333.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Okatsu K, Uno M, Koyano F, Go E, Kimura M, Oka T et al. A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment. J Biol Chem 2013; 288: 36372–36384.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L et al. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat Commun 2013; 4: 1982.

    CAS  PubMed  Google Scholar 

  57. Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2012; 2: 120080.

    PubMed  PubMed Central  Google Scholar 

  58. Trempe JF, Sauve V, Grenier K, Seirafi M, Tang MY, Menade M et al. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 2013; 340: 1451–1455.

    CAS  PubMed  Google Scholar 

  59. Hristova VA, Beasley SA, Rylett RJ, Shaw GS . Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J Biol Chem 2009; 284: 14978–14986.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J 2014; 460: 127–139.

    CAS  PubMed  Google Scholar 

  61. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 2013; 496: 372–376.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 2011; 20: 1726–1737.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ziviani E, Tao RN, Whitworth AJ . Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 2010; 107: 5018–5023.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006; 441: 1162–1166.

    CAS  PubMed  Google Scholar 

  65. Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 2014; 205: 143–153.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kazlauskaite A, Martinez-Torres RJ, Wilkie S, Kumar A, Peltier J, Gonzalez A et al. Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep 2015; 16: 939–954.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 2014; 510: 162–166.

    CAS  PubMed  Google Scholar 

  68. Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 2014; 56: 360–375.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ordureau A, Heo JM, Duda DM, Paulo JA, Olszewski JL, Yanishevski D et al. Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci USA 2015; 112: 6637–6642.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Komander D, Rape M . The ubiquitin code. Annu Rev Biochem 2012; 81: 203–229.

    CAS  PubMed  Google Scholar 

  71. Cornelissen T, Haddad D, Wauters F, Van Humbeeck C, Mandemakers W, Koentjoro B et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet 2014; 23: 5227–5242.

    CAS  PubMed  Google Scholar 

  72. Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 2014; 510: 370–375.

    CAS  PubMed  Google Scholar 

  73. Cunningham CN, Baughman JM, Phu L, Tea JS, Yu C, Coons M et al. USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Nat Cell Biol 2015; 17: 160–169.

    CAS  PubMed  Google Scholar 

  74. Liang JR, Martinez A, Lane JD, Mayor U, Clague MJ, Urbe S . USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death. EMBO Rep 2015; 16: 618–627.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Durcan TM, Tang MY, Perusse JR, Dashti EA, Aguileta MA, McLelland GL et al. USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J 2014; 33: 2473–2491.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12: 119–131.

    CAS  PubMed  Google Scholar 

  77. Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ . p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 2010; 6: 1090–1106.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Wong YC, Holzbaur EL . Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci USA 2014; 111: E4439–E4448.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW . The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol Cell 2015; 60: 7–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T . LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 2004; 117: 2805–2812.

    CAS  PubMed  Google Scholar 

  81. Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K et al. Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension. J Biol Chem 2001; 276: 19548–19554.

    CAS  PubMed  Google Scholar 

  82. Murakawa T, Yamaguchi O, Hashimoto A, Hikoso S, Takeda T, Oka T et al. Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat Commun 2015; 6: 7527.

    PubMed  Google Scholar 

  83. Lamb CA, Yoshimori T, Tooze SA . The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol 2013; 14: 759–774.

    CAS  PubMed  Google Scholar 

  84. Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y . Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem 1991; 266: 17707–17712.

    CAS  PubMed  Google Scholar 

  85. Boland ML, Chourasia AH, Macleod KF . Mitochondrial dysfunction in cancer. Front Oncol 2013; 3: 292.

    PubMed  PubMed Central  Google Scholar 

  86. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 2010; 11: 45–51.

    CAS  PubMed  Google Scholar 

  87. Schwarten M, Mohrluder J, Ma P, Stoldt M, Thielmann Y, Stangler T et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy 2009; 5: 690–698.

    CAS  PubMed  Google Scholar 

  88. Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S, Gustafsson AB . Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem 2012; 287: 19094–19104.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC et al. BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem 2000; 275: 1439–1448.

    CAS  PubMed  Google Scholar 

  90. Zhu Y, Massen S, Terenzio M, Lang V, Chen-Lindner S, Eils R et al. Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol Chem 2013; 288: 1099–1113.

    CAS  PubMed  Google Scholar 

  91. Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 2012; 14: 177–185.

    PubMed  Google Scholar 

  92. Wu W, Tian W, Hu Z, Chen G, Huang L, Li W et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 2014; 15: 566–575.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell 2014; 54: 362–377.

    CAS  PubMed  Google Scholar 

  94. Liu L, Sakakibara K, Chen Q, Okamoto K . Receptor-mediated mitophagy in yeast and mammalian systems. Cell Res 2014; 24: 787–795.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wu H, Xue D, Chen G, Han Z, Huang L, Zhu C et al. The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy. Autophagy 2014; 10: 1712–1725.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Lu W, Karuppagounder SS, Springer DA, Allen MD, Zheng L, Chao B et al. Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder. Nat Commun 2014; 5: 4930.

    CAS  PubMed  Google Scholar 

  97. Lo SC, Hannink M . PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex. J Biol Chem 2006; 281: 37893–37903.

    CAS  PubMed  Google Scholar 

  98. Wang Z, Jiang H, Chen S, Du F, Wang X . The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 2012; 148: 228–243.

    CAS  PubMed  Google Scholar 

  99. Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 2013; 39: 443–453.

    CAS  PubMed  Google Scholar 

  100. Yun J, Puri R, Yang H, Lizzio MA, Wu C, Sheng ZH et al. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife 2014; 3: e01958.

    PubMed  PubMed Central  Google Scholar 

  101. Fu M, St-Pierre P, Shankar J, Wang PT, Joshi B, Nabi IR . Regulation of mitophagy by the Gp78 E3 ubiquitin ligase. Mol Biol Cell 2013; 24: 1153–1162.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Orvedahl A, Sumpter R Jr, Xiao G, Ng A, Zou Z, Tang Y et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 2011; 480: 113–117.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Green DR, Galluzzi L, Kroemer G . Cell biology. Metabolic control of cell death. Science 2014; 345: 1250256.

    PubMed  PubMed Central  Google Scholar 

  104. Li MX, Dewson G . Mitochondria and apoptosis: emerging concepts. F1000Prime Rep 2015; 7: 42.

    PubMed  PubMed Central  Google Scholar 

  105. Czabotar PE, Lessene G, Strasser A, Adams JM . Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15: 49–63.

    CAS  PubMed  Google Scholar 

  106. Youle RJ, Strasser A . The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9: 47–59.

    CAS  PubMed  Google Scholar 

  107. Taylor RC, Cullen SP, Martin SJ . Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 2008; 9: 231–241.

    CAS  PubMed  Google Scholar 

  108. Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. Embo J 2007; 26: 2527–2539.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122: 927–939.

    CAS  PubMed  Google Scholar 

  110. Lindqvist LM, Heinlein M, Huang DC, Vaux DL . Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak. Proc Natl Acad Sci USA 2014; 111: 8512–8517.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hollville E, Carroll RG, Cullen SP, Martin SJ . Bcl-2 family proteins participate in mitochondrial quality control by regulating Parkin/PINK1-dependent mitophagy. Mol Cell 2014; 55: 451–466.

    CAS  PubMed  Google Scholar 

  112. Carroll RG, Hollville E, Martin SJ . Parkin sensitizes toward apoptosis induced by mitochondrial depolarization through promoting degradation of Mcl-1. Cell Rep 2014; 9: 1538–1553.

    CAS  PubMed  Google Scholar 

  113. Johnson BN, Berger AK, Cortese GP, Lavoie MJ . The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc Natl Acad Sci USA 2012; 109: 6283–6288.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Charan RA, Johnson BN, Zaganelli S, Nardozzi JD, LaVoie MJ . Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin. Cell Death Dis 2014; 5: e1313.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Chen D, Gao F, Li B, Wang H, Xu Y, Zhu C et al. Parkin mono-ubiquitinates Bcl-2 and regulates autophagy. J Biol Chem 2010; 285: 38214–38223.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang C, Lee S, Peng Y, Bunker E, Giaime E, Shen J et al. PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol 2014; 24: 1854–1865.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 1998; 187: 1477–1485.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1: 489–495.

    CAS  PubMed  Google Scholar 

  119. Radogna F, Cerella C, Gaigneaux A, Christov C, Dicato M, Diederich M . Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma. Oncogene 2015; 35: 2839–2853.

    Google Scholar 

  120. Xia M, Meng G, Jiang A, Chen A, Dahlhaus M, Gonzalez P et al. Mitophagy switches cell death from apoptosis to necrosis in NSCLC cells treated with oncolytic measles virus. Oncotarget 2014; 5: 3907–3918.

    PubMed  PubMed Central  Google Scholar 

  121. Tait SW, Oberst A, Quarato G, Milasta S, Haller M, Wang R et al. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep 2013; 5: 878–885.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Remijsen Q, Goossens V, Grootjans S, Van den Haute C, Vanlangenakker N, Dondelinger Y et al. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis 2014; 5: e1004.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Lu W, Sun J, Yoon JS, Zhang Y, Zheng L, Murphy E et al. Mitochondrial protein PGAM5 regulates mitophagic protection against cell necroptosis. PLoS One 2016; 11: e0147792.

    PubMed  PubMed Central  Google Scholar 

  124. Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 2010; 15: 887–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Detmer SA, Chan DC . Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 2007; 8: 870–879.

    CAS  PubMed  Google Scholar 

  126. Otera H, Mihara K . Molecular mechanisms and physiologic functions of mitochondrial dynamics. J Biochem 2011; 149: 241–251.

    CAS  PubMed  Google Scholar 

  127. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW . Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 2010; 19: 4861–4870.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L . The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One 2010; 5: e10054.

    PubMed  PubMed Central  Google Scholar 

  129. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 2010; 191: 1367–1380.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27: 433–446.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Wang H, Song P, Du L, Tian W, Yue W, Liu M et al. Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem 2011; 286: 11649–11658.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 2011; 147: 893–906.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Birsa N, Norkett R, Wauer T, Mevissen TE, Wu HC, Foltynie T et al. Lysine 27 ubiquitination of the mitochondrial transport protein Miro is dependent on serine 65 of the Parkin ubiquitin ligase. J Biol Chem 2014; 289: 14569–14582.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Fransson S, Ruusala A, Aspenstrom P . The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem Biophys Res Commun 2006; 344: 500–510.

    CAS  PubMed  Google Scholar 

  135. Landes T, Emorine LJ, Courilleau D, Rojo M, Belenguer P, Arnaune-Pelloquin L . The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms. EMBO Rep 2010; 11: 459–465.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Quinsay MN, Lee Y, Rikka S, Sayen MR, Molkentin JD, Gottlieb RA et al. Bnip3 mediates permeabilization of mitochondria and release of cytochrome c via a novel mechanism. J Mol Cell Cardiol 2010; 48: 1146–1156.

    CAS  PubMed  Google Scholar 

  137. Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A . Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 2003; 37: 735–749.

    CAS  PubMed  Google Scholar 

  138. Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I et al. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 2010; 42: 77–82.

    CAS  PubMed  Google Scholar 

  139. Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E, Raheja R et al. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet 2014; 46: 588–594.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Ko HS, von Coelln R, Sriram SR, Kim SW, Chung KK, Pletnikova O et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J Neurosci: Off J Soc Neurosci 2005; 25: 7968–7978.

    CAS  Google Scholar 

  141. da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol 2009; 11: 1370–1375.

    PubMed  PubMed Central  Google Scholar 

  142. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 2004; 279: 18614–18622.

    CAS  PubMed  Google Scholar 

  143. Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A et al. Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Investig 2011; 121: 3701–3712.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Liu K, Li F, Han H, Chen Y, Mao Z, Luo J et al. Parkin regulates the activity of pyruvate kinase M2. J Biol Chem 2016; 291: 10307–10317.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Sabharwal SS, Schumacker PT . Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat Rev Cancer 2014; 14: 709–721.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Wallace DC . Mitochondria and cancer. Nat Rev Cancer 2012; 12: 685–698.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Dexter DT, Sian J, Rose S, Hindmarsh JG, Mann VM, Cooper JM et al. Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann Neurol 1994; 35: 38–44.

    CAS  PubMed  Google Scholar 

  148. Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA et al. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 2003; 12: 2277–2291.

    CAS  PubMed  Google Scholar 

  149. Hyun DH, Lee M, Hattori N, Kubo S, Mizuno Y, Halliwell B et al. Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J Biol Chem 2002; 277: 28572–28577.

    CAS  PubMed  Google Scholar 

  150. Yakes FM, Van Houten B . Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 1997; 94: 514–519.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT . Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 2008; 28: 718–731.

    CAS  PubMed  Google Scholar 

  152. Semenza GL . Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 2009; 19: 12–16.

    CAS  PubMed  Google Scholar 

  153. Jones RG, Thompson CB . Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 2009; 23: 537–548.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 2006; 15: 883–895.

    CAS  PubMed  Google Scholar 

  155. Halazonetis TD, Gorgoulis VG, Bartek J . An oncogene-induced DNA damage model for cancer development. Science 2008; 319: 1352–1355.

    CAS  PubMed  Google Scholar 

  156. Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller MC, Shaikh N et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 2013; 494: 492–496.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Plun-Favreau H, Lewis PA, Hardy J, Martins LM, Wood NW . Cancer and neurodegeneration: between the devil and the deep blue sea. PLoS Genet 2010; 6: e1001257.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Morris LG, Veeriah S, Chan TA . Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene 2010; 29: 3453–3464.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K et al. PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci USA 2010; 107: 15145–15150.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012; 30: 2956–2962.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Mulholland PJ, Fiegler H, Mazzanti C, Gorman P, Sasieni P, Adams J et al. Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme. Cell Cycle 2006; 5: 783–791.

    CAS  PubMed  Google Scholar 

  162. Viotti J, Duplan E, Caillava C, Condat J, Goiran T, Giordano C et al. Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity. Oncogene 2014; 33: 1764–1775.

    CAS  PubMed  Google Scholar 

  163. Lee KS, Wu Z, Song Y, Mitra SS, Feroze AH, Cheshier SH et al. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev 2013; 27: 2642–2647.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 2013; 45: 279–284.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. West AB, Kapatos G, O'Farrell C, Gonzalez-de-Chavez F, Chiu K, Farrer MJ et al. N-myc regulates parkin expression. J Biol Chem 2004; 279: 28896–28902.

    CAS  PubMed  Google Scholar 

  166. Strieder V, Lutz W . Regulation of N-myc expression in development and disease. Cancer Lett 2002; 180: 107–119.

    CAS  PubMed  Google Scholar 

  167. Wang M, Suzuki T, Kitada T, Asakawa S, Minoshima S, Shimizu N et al. Developmental changes in the expression of parkin and UbcR7, a parkin-interacting and ubiquitin-conjugating enzyme, in rat brain. J Neurochem 2001; 77: 1561–1568.

    CAS  PubMed  Google Scholar 

  168. Kitada T, Asakawa S, Minoshima S, Mizuno Y, Shimizu N . Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome: Off J Int Mamm Genome Soc 2000; 11: 417–421.

    CAS  Google Scholar 

  169. Kaminskyy VO, Piskunova T, Zborovskaya IB, Tchevkina EM, Zhivotovsky B . Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation. Autophagy 2012; 8: 1032–1044.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M, Nitsch R et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun 2014; 5: 3056.

    PubMed  Google Scholar 

  171. Thomas KJ, Jacobson MR . Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model. PLoS One 2012; 7: e45319.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Hung JY, Hsu YL, Li CT, Ko YC, Ni WC, Huang MS et al. 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem 2009; 57: 9809–9816.

    CAS  PubMed  Google Scholar 

  173. Dasgupta S, Soudry E, Mukhopadhyay N, Shao C, Yee J, Lam S et al. Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation. J Cell Physiol 2012; 227: 2451–2460.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Noviello C, Courjal F, Theillet C . Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion. Clin Cancer Res 1996; 2: 1601–1606.

    CAS  PubMed  Google Scholar 

  175. Orphanos V, McGown G, Hey Y, Boyle JM, Santibanez-Koref M . Proximal 6q, a region showing allele loss in primary breast cancer. Br J Cancer 1995; 71: 290–293.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012; 486: 395–399.

    CAS  PubMed  Google Scholar 

  177. Courjal F, Louason G, Speiser P, Katsaros D, Zeillinger R, Theillet C . Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer 1996; 69: 247–253.

    CAS  PubMed  Google Scholar 

  178. Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J . Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 1994; 57: 353–361.

    CAS  PubMed  Google Scholar 

  179. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993; 8: 2127–2133.

    CAS  PubMed  Google Scholar 

  180. Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C et al. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 1994; 54: 1812–1817.

    CAS  PubMed  Google Scholar 

  181. Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Investig 2013; 123: 1068–1081.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A et al. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: autophagy drives compartment-specific oncogenesis. Cell Cycle 2010; 9: 3534–3551.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE, Lin Z et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. Cell Cycle 2011; 10: 4065–4073.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Chourasia AH, Tracy K, Frankenberger C, Boland ML, Sharifi MN, Drake LE et al. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep 2015; 16: 1145–1163.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Shen Y, Li DD, Wang LL, Deng R, Zhu XF . Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy 2008; 4: 1067–1068.

    CAS  PubMed  Google Scholar 

  186. Alvero AB, Montagna MK, Holmberg JC, Craveiro V, Brown D, Mor G . Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells. Mol Cancer Ther 2011; 10: 1385–1393.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kandala PK, Srivastava SK . Regulation of macroautophagy in ovarian cancer cells in vitro and in vivo by controlling glucose regulatory protein 78 and AMPK. Oncotarget 2012; 3: 435–449.

    PubMed  PubMed Central  Google Scholar 

  188. Chourasia AH, Boland ML, Macleod KF . Mitophagy and cancer. Cancer Metab 2015; 3: 4.

    PubMed  PubMed Central  Google Scholar 

  189. Lai J, Flanagan J, Phillips WA, Chenevix-Trench G, Arnold J . Analysis of the candidate 8p21 tumour suppressor, BNIP3L, in breast and ovarian cancer. Br J Cancer 2003; 88: 270–276.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Martinez-Outschoorn UE, Balliet RM, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F et al. Hereditary ovarian cancer and two-compartment tumor metabolism: epithelial loss of BRCA1 induces hydrogen peroxide production, driving oxidative stress and NFkappaB activation in the tumor stroma. Cell Cycle 2012; 11: 4152–4166.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Helland A, Anglesio MS, George J, Cowin PA, Johnstone CN, House CM et al. Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers. PLoS One 2011; 6: e18064.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Moller H, Mellemkjaer L, McLaughlin JK, Olsen JH . Occurrence of different cancers in patients with Parkinson's disease. BMJ 1995; 310: 1500–1501.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Zanchetta LM, Garcia A, Lyng F, Walsh J, Murphy JE . Mitophagy and mitochondrial morphology in human melanoma-derived cells post exposure to simulated sunlight. Int J Radiat Biol 2011; 87: 506–517.

    CAS  PubMed  Google Scholar 

  194. Christensen C, Bartkova J, Mistrik M, Hall A, Lange MK, Ralfkiaer U et al. A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility. Nat Commun 2014; 5: 5348.

    CAS  PubMed  Google Scholar 

  195. Maes H, Agostinis P . Autophagy and mitophagy interplay in melanoma progression. Mitochondrion 2014; 19 Pt A: 58–68.

    PubMed  Google Scholar 

  196. Marino ML, Pellegrini P, Di Lernia G, Djavaheri-Mergny M, Brnjic S, Zhang X et al. Autophagy is a protective mechanism for human melanoma cells under acidic stress. J Biol Chem 2012; 287: 30664–30676.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Sheen JH, Zoncu R, Kim D, Sabatini DM . Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 2011; 19: 613–628.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Tormo D, Checinska A, Alonso-Curbelo D, Perez-Guijarro E, Canon E, Riveiro-Falkenbach E et al. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 2009; 16: 103–114.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Xie X, White EP, Mehnert JM . Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLoS One 2013; 8: e55096.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Maes H, Van Eygen S, Krysko DV, Vandenabeele P, Nys K, Rillaerts K et al. BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton. Cell Death Dis 2014; 5: e1127.

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Hu HH, Kannengiesser C, Lesage S, Andre J, Mourah S, Michel L et al. PARKIN inactivation links Parkinson's disease to melanoma. J Natl Cancer Inst 2016; 108: djv340.

    Google Scholar 

  202. Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 2013; 27: 1447–1461.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013; 504: 296–300.

    CAS  PubMed  Google Scholar 

  204. Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015; 350: 1391–1396.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Paul Ekert and Jamie Fletcher for advice and discussions in the preparation of the manuscript. GD is supported by an Australian Research Council Future Fellowship (#FT100100791). Supported through operational infrastructure grants through the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS.

Author information

Authors and Affiliations

  1. Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    J P Bernardini & G Dewson

  2. Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria, Australia

    J P Bernardini & G Dewson

  3. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

    M Lazarou

Authors
  1. J P Bernardini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Lazarou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Dewson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Dewson.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bernardini, J., Lazarou, M. & Dewson, G. Parkin and mitophagy in cancer. Oncogene 36, 1315–1327 (2017). https://doi.org/10.1038/onc.2016.302

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2016.302

This article is cited by

Search

Advanced search

Quick links