The three ‘P’s of mitophagy: PARKIN.; PINK1.; and post-translational modifications
Open accessAbstract
Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control.
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The most important and better understood pathway to mitophagy is the canonical PINK1/PARKIN pathway.
“There are apparently several pathways to mitophagy [169,170], but the most important and the better understood one is the canonical PINK1/PARKIN pathway [171,172,173,174,175,176].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [171]
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- Authors
- Durcan, T. M., & Fon, E. A.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Corresponding author
- Fon, Edward A.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-05-15
- Volume
- 29
- Issue
- 10
- Pages
- 989-999
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4441056
- OpenAlex
- W1884950180
- Cited by
- 400
- References
- 96
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 29 · 2023: 40 · 2022: 38 · 2021: 39 · 2020: 42 · 2019: 36 · 2018: 32 · 2017: 46 · 2016: 37 · 2015: 10
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship@McGill (McGill) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by-nc)
- Funders
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec-Santé
- Parkinson's Society of Canada
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- mitophagy, PINK1, Parkin, post-translational modification, mitochondrial quality control, E3 ubiquitin ligase, ubiquitination, phosphorylation, deubiquitinase, USP8, USP15, USP30, Parkinson's disease
- MeSH terms
- PTEN-Induced Putative Kinase, Enzyme Activation, Humans, Mitochondria, Parkinson Disease, Phosphorylation, Protein Kinases, Protein Processing, Post-Translational, Ubiquitin-Protein Ligases, Ubiquitination, Mitophagy
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