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Cellular and Molecular Life Sciences

, Volume 76, Issue 23, pp 4589–4611 | Cite as

Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond

  • Andrew N. Bayne
  • Jean-François TrempeEmail author
Review

Abstract

Parkinson’s disease (PD) is a degenerative movement disorder resulting from the loss of specific neuron types in the midbrain. Early environmental and pathophysiological studies implicated mitochondrial damage and protein aggregation as the main causes of PD. These findings are now vindicated by the characterization of more than 20 genes implicated in rare familial forms of the disease. In particular, two proteins encoded by the Parkin and PINK1 genes, whose mutations cause early-onset autosomal recessive PD, function together in a mitochondrial quality control pathway. In this review, we will describe recent development in our understanding of their mechanisms of action, structure, and function. We explain how PINK1 acts as a mitochondrial damage sensor via the regulated proteolysis of its N-terminus and the phosphorylation of ubiquitin tethered to outer mitochondrial membrane proteins. In turn, phospho-ubiquitin recruits and activates Parkin via conformational changes that increase its ubiquitin ligase activity. We then describe how the formation of polyubiquitin chains on mitochondria triggers the recruitment of the autophagy machinery or the formation of mitochondria-derived vesicles. Finally, we discuss the evidence for the involvement of these mechanisms in physiological processes such as immunity and inflammation, as well as the links to other PD genes.

Keywords

Parkinson Ubiquitin Kinase Parkin PINK1 Mitochondria 

Notes

Acknowledgements

We would like to thank the members of the Trempe, Gehring, Fon and Durcan labs for stimulating discussions that forged our understanding of the Parkin/PINK1 pathway. A.B. is supported by a Healthy Brain for Healthy LivesCanada First Research Excellence Fund (HBHL-CFREF) (No. 1c-II-5) studentship at McGill University. J.-F.T. is supported by a Tier 2 Canada Research Chair (No. 950-229792) and research grants from the Canadian Institutes of Health Research (No. PJT-153274), Natural Sciences and Engineering Research Council (No. RGPIN-06497), Parkinson Canada (No. 2017-1277), the Michael J. Fox Foundation (No. 14681), and the HBHL-CFREF.

Compliance with ethical standards

Conflict of interest

ANB declares no conflicts of interest. J-FT is a consultant for Mitokinin Inc. and a founding member of M4ND Pharma Inc.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics and Centre for Structural BiologyMcGill UniversityMontrealCanada

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