Cited by 3,082Autophagy in Disease and TherapyMitochondrial Function and PathologyCell death mechanisms and regulation

The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy

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Abstract

Accumulation of depolarized mitochondria within beta-cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a 'kiss and run' pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (delta psi(m)) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non-fusing mitochondria that were found to have reduced delta psi(m) and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1(K38A) or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre-proteolysis stage reveal that before autophagy mitochondria lose delta psi(m) and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.

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Metadata

Authors
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey, B. E., & Shirihai, O. S.
Affiliations
  • Tufts University (US)
  • Boston University (US)
  • Billerica Public Library (US)
  • Harvard University (US)
Corresponding author
Shirihai, Orian S
Venue
The EMBO Journal
Published
2008-01-17
Volume
27
Issue
2
Pages
433-446
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
OpenAlex
W2139636031
Cited by
3,082
References
39
Citations by year
2026: 107 · 2025: 144 · 2024: 207 · 2023: 167 · 2022: 186 · 2021: 217 · 2020: 204 · 2019: 176 · 2018: 194 · 2017: 193 · 2016: 188 · 2015: 185 · 2014: 165 · 2013: 171 · 2012: 202
FWCI
91.10
Type
journal article
Language
en
Open access
Locations
  • The EMBO Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • National Science Foundation (0215829)
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL071629)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074778)
  • National Center for Research Resources (P41RR001395)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
mitochondrial fission, mitochondrial fusion, kiss-and-run, mitophagy, OPA1, Drp1, Fis1, pancreatic beta cells, insulin secretion, mitochondrial membrane potential, oxidative stress, diabetes mellitus, mitochondrial segregation
MeSH terms
Autophagy-Related Protein 5, Insulin Secretion, Animals, Autophagy, Cell Line, Genotype, Insulin, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Mitochondria, Models, Biological, Mutation, Reactive Oxygen Species, Microscopy, Confocal, GTP Phosphohydrolases, Mitochondrial Proteins, Green Fluorescent Proteins, Insulin-Secreting Cells, Mice, Membrane Potential, Mitochondrial

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