Article
- The EMBO Journal (2008) 27, 433 - 446
- doi:10.1038/sj.emboj.7601963
Published online: 17 January 2008
Subject Categories:
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Gilad Twig1,6, Alvaro Elorza1,6, Anthony J A Molina1,2, Hibo Mohamed1, Jakob D Wikstrom1, Gil Walzer1, Linsey Stiles1, Sarah E Haigh1, Steve Katz1, Guy Las1, Joseph Alroy3, Min Wu4, Bénédicte F Py5, Junying Yuan5, Jude T Deeney2, Barbara E Corkey2 and Orian S Shirihai1
- Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA
- Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- Department of Pathology Tufts—NEMC and School of Veterinary Medicine, Boston, MA, USA
- Seahorse Bioscience, North Billerica, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
Correspondence to:
Orian S Shirihai, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA. Tel.: +1 617 230 8570; Fax: +1 617 636 6738; E-mail: orian.shirihai@tufts.edu
6These authors contributed equally to this work
Received 9 March 2007; Accepted 20 November 2007
Abstract
Accumulation of depolarized mitochondria within 
-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 (
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 m 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 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.
Keywords:
- autophagy,
- -cell,
- fission,
- fusion,
- mitochondria
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