Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization

Ann Cassidy-Stone, Jerry E. Chipuk, Elena Ingerman, Cheng Song, Choong Yoo, Tomomi Kuwana, Mark J. Kurth, Jared T. Shaw, Jenny E. Hinshaw, Douglas R. Green, Jodi Nunnari

Research output: Contribution to journalArticlepeer-review

729 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)193-204
Number of pages12
JournalDevelopmental Cell
Volume14
Issue number2
DOIs
StatePublished - Feb 12 2008

Keywords

  • CELLBIO
  • CELLCYCLE
  • CHEMBIO

ASJC Scopus subject areas

  • Developmental Biology

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