The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria
Open accessAbstract
Defective mitochondria exert deleterious effects on host cells. To manage this risk, mitochondria display several lines of quality control mechanisms: mitochondria-specific chaperones and proteases protect against misfolded proteins at the molecular level, and fission/fusion and mitophagy segregate and eliminate damage at the organelle level. An increase in unfolded proteins in mitochondria activates a mitochondrial unfolded protein response (UPR(mt)) to increase chaperone production, while the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin, whose mutations cause familial Parkinson disease, remove depolarized mitochondria through mitophagy. It is unclear, however, if there is a connection between those different levels of quality control (QC). Here, we show that the expression of unfolded proteins in the matrix causes the accumulation of PINK1 on energetically healthy mitochondria, resulting in mitochondrial translocation of PARK2, mitophagy and subsequent reduction of unfolded protein load. Also, PINK1 accumulation is greatly enhanced by the knockdown of the LONP1 protease. We suggest that the accumulation of unfolded proteins in mitochondria is a physiological trigger of mitophagy.
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LONP1 degrades ΔOTC.
“Consistent with LONP1 degrading ΔOTC39,40”
From Disuse-associated loss of the protease Lonp1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength (2022) · cites this paper as [39]
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“Parkin activation relieves mitochondrial unfolded protein stress presumably through the mitophagic removal of mitochondria with accumulated unfolded proteins (Jin and Youle, 2013).”
Background
- Authors
- Jin, S. M., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Youle, Richard J
- ORCID
- Youle, Richard J
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2013-11-03
- Volume
- 9
- Issue
- 11
- Pages
- 1750-1757
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC4028334
- OpenAlex
- W2056043482
- Cited by
- 411
- References
- 32
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 24 · 2023: 23 · 2022: 38 · 2021: 44 · 2020: 34 · 2019: 30 · 2018: 41 · 2017: 28 · 2016: 44 · 2015: 34 · 2014: 20 · 2013: 1
- FWCI
- 24.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PINK1, mitophagy, mitochondrial unfolded protein response, mitochondrial quality control, misfolded proteins, mitochondrial matrix, mitochondrial translocation, Parkinson's disease, mitochondrial depolarization, mitochondrial chaperone
- MeSH terms
- PTEN-Induced Putative Kinase, HeLa Cells, Humans, Mitochondria, Ornithine Carbamoyltransferase, Protein Kinases, Gene Deletion, Protein Folding, Ubiquitin-Protein Ligases, Membrane Potential, Mitochondrial, Unfolded Protein Response, Protein Unfolding, Mitophagy
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