Parkin and mitophagy in cancer.
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.
Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria, Australia.
J P
JP
Bernardini
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
M
M
Lazarou
Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria, Australia.
G
G
Dewson
D000818:Animals; D004734:Energy Metabolism; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein