Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.
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.
Cassidy-Stone
Ann
A
Section of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
Chipuk
Jerry E
JE
Ingerman
Elena
E
Song
Cheng
C
Yoo
Choong
C
Kuwana
Tomomi
T
Kurth
Mark J
MJ
Shaw
Jared T
JT
Hinshaw
Jenny E
JE
Green
Douglas R
DR
Nunnari
Jodi
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D052999:Quinazolinones; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D034281:Dynamins