Cited by 1,200Mitochondrial Function and PathologyCell death mechanisms and regulationAutophagy in Disease and Therapy

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

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Cassidy-Stone, Ann, Chipuk, Jerry E., Ingerman, Elena, Song, Cheng, Yoo, Choong, Kuwana, Tomomi, Kurth, Mark J., Shaw, Jared T. +3 more·2008·Developmental Cell

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.

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Crossref · 10.1016/j.devcel.2007.11.019

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Authors
Cassidy-Stone, A., Chipuk, J. E., Ingerman, E., Song, C., Yoo, C., Kuwana, T., Kurth, M. J., Shaw, J. T., Hinshaw, J. E., Green, D. R., & Nunnari, J.
Affiliations
  • University of California, Davis (US)
  • St. Jude Children's Research Hospital (US)
  • University of Iowa (US)
  • Broad Institute (US)
  • National Institutes of Health (US)
Corresponding author
Nunnari, Jodi
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2008-02
Volume
14
Issue
2
Pages
193-204
ISSN
1534-5807 (ISSN-L)
OpenAlex
W2059009119
Cited by
1,200
References
61
Citations by year
2026: 61 · 2025: 63 · 2024: 86 · 2023: 71 · 2022: 64 · 2021: 73 · 2020: 83 · 2019: 68 · 2018: 85 · 2017: 90 · 2016: 78 · 2015: 63 · 2014: 66 · 2013: 61 · 2012: 56
FWCI
17.85
Type
journal article
Language
en
Open access
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health (AI40646, 1 R01 EY015924, CA69301, GM52735)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial division, dynamin, Mdivi-1, mitochondrial outer membrane permeabilization, Bax, Bak, Bid, cytochrome c release, apoptosis, Drp1, chemical inhibitors, stroke, myocardial infarction, neurodegenerative diseases
MeSH terms
Animals, Chlorocebus aethiops, Flow Cytometry, HeLa Cells, Humans, Mitochondria, Permeability, Saccharomyces cerevisiae, Structure-Activity Relationship, Apoptosis, COS Cells, Dynamins, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mitochondrial Membranes, Quinazolinones

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