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 journalArticle

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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

Fingerprint

Dynamins
Mitochondrial Membranes
Apoptosis
Membranes
Mitochondria
Mitochondrial Dynamics
Cytochromes c
Fusion reactions
Neurodegenerative diseases
Apoptosis Regulatory Proteins
Yeast
Mitochondrial Proteins
Cardiomyopathies
Neurodegenerative Diseases
Cells
Yeasts
Stroke
Myocardial Infarction
Proteins

Keywords

  • CELLBIO
  • CELLCYCLE
  • CHEMBIO

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization. / Cassidy-Stone, Ann; Chipuk, Jerry E.; Ingerman, Elena; Song, Cheng; Yoo, Choong; Kuwana, Tomomi; Kurth, Mark J.; Shaw, Jared T.; Hinshaw, Jenny E.; Green, Douglas R.; Nunnari, Jodi.

In: Developmental Cell, Vol. 14, No. 2, 12.02.2008, p. 193-204.

Research output: Contribution to journalArticle

Cassidy-Stone, A, Chipuk, JE, Ingerman, E, Song, C, Yoo, C, Kuwana, T, Kurth, MJ, Shaw, JT, Hinshaw, JE, Green, DR & Nunnari, J 2008, 'Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization', Developmental Cell, vol. 14, no. 2, pp. 193-204. https://doi.org/10.1016/j.devcel.2007.11.019
Cassidy-Stone, Ann ; Chipuk, Jerry E. ; Ingerman, Elena ; Song, Cheng ; Yoo, Choong ; Kuwana, Tomomi ; Kurth, Mark J. ; Shaw, Jared T. ; Hinshaw, Jenny E. ; Green, Douglas R. ; Nunnari, Jodi. / Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization. In: Developmental Cell. 2008 ; Vol. 14, No. 2. pp. 193-204.
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