Mitochondrial fission facilitates the selective mitophagy of protein aggregates
Open accessAbstract
Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1-Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing ΔOTC, it does not decrease the rate of ΔOTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for ΔOTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1-Parkin activity.
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Mitochondrial fission is necessary for subsequent mitophagy to dissipate dysfunctional parts from the mitochondrial network.
“Mitochondrial fission is necessary for subsequent mitophagy to dissipate dysfunctional parts from the mitochondrial network (90).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [90]
Mitophagy is intricately linked to mitochondrial dynamics.
“Mitophagy is intricately linked to mitochondrial dynamics [180,181,182].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [182]
Dysfunctional mitochondrial subdomains can be segregated from mitochondria and degraded by autophagy under stress.
“dysfunctional mitochondrial subdomains can be segregated from mitochondria and degraded by autophagy under stress54.”
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 [54]
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- Authors
- Burman, J. L., Pickles, S., Wang, C., Sekine, S., Vargas, J. N. S., Zhang, Z., Youle, A. M., Nezich, C. L., Wu, X., Hammer, J. A., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Youle, Richard J.
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2017-09-11
- Volume
- 216
- Issue
- 10
- Pages
- 3231-3247
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC5626535
- OpenAlex
- W2755224635
- Cited by
- 479
- References
- 47
- Citations by year
- 2026: 33 · 2025: 42 · 2024: 63 · 2023: 57 · 2022: 55 · 2021: 67 · 2020: 74 · 2019: 46 · 2018: 35 · 2017: 5
- FWCI
- 34.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- 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
- mitochondrial fission, mitophagy, PINK1, Parkin, Drp1, protein aggregation, mitochondrial unfolded protein response, ornithine transcarbamylase, optineurin, LC3, ubiquitin, actinonin
- MeSH terms
- PTEN-Induced Putative Kinase, HeLa Cells, Humans, Microtubule-Associated Proteins, Models, Biological, Ornithine Carbamoyltransferase, Protein Kinases, Cell Cycle Proteins, GTP Phosphohydrolases, Mitochondrial Proteins, Ubiquitin, Membrane Transport Proteins, Dynamins, Transcription Factor TFIIIA, Ubiquitin-Protein Ligases, HEK293 Cells, Mitochondrial Dynamics, Mitophagy, Protein Aggregates
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