Fission and selective fusion govern mitochondrial segregation and elimination by autophagy

Gilad Twig, Alvaro Elorza, Anthony J A Molina, Hibo Mohamed, Jakob D. Wikstrom, Gil Walzer, Linsey Stiles, Sarah E. Haigh, Steve Katz, Guy Las, Joseph Alroy, Min Wu, Bénédicte F. Py, Junying Yuan, Jude T. Deeney, Barbara E. Corkey, Orian S. Shirihai

Research output: Contribution to journalArticlepeer-review

1884 Citations (Scopus)

Abstract

Accumulation of depolarized mitochondria within β-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 (Δψm) 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 Δψm and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1K38A 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 Δψm 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.

Original languageEnglish
Pages (from-to)433-446
Number of pages14
JournalEMBO Journal
Volume27
Issue number2
DOIs
Publication statusPublished - 23 Jan 2008

Keywords

  • Autophagy
  • Fission
  • Fusion
  • Mitochondria
  • β-cell

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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