Journal
DEVELOPMENTAL CELL
Volume 14, Issue 2, Pages 193-204Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2007.11.019
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Funding
- NCI NIH HHS [CA69301] Funding Source: Medline
- NEI NIH HHS [1 R01 EY015924, R01 EY015924-01, R01 EY015924-03, R01 EY015924, R01 EY015924-02] Funding Source: Medline
- NIAID NIH HHS [R01 AI040646, AI40646] Funding Source: Medline
- NIGMS NIH HHS [R01 GM052735, R01 GM062942, R37 GM052735, GM52735, R01 GM062942-07] Funding Source: Medline
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Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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