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Parkin and mitophagy in cancer

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.

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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.

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

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