Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors

Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascade...

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Published inNature chemical biology Vol. 1; no. 4; pp. 223 - 232
Main Authors Kagan, Valerian E, Tyurin, Vladimir A, Jiang, Jianfei, Tyurina, Yulia Y, Ritov, Vladimir B, Amoscato, Andrew A, Osipov, Anatoly N, Belikova, Natalia A, Kapralov, Alexandr A, Kini, Vidisha, Vlasova, Irina I, Zhao, Qing, Zou, Meimei, Di, Peter, Svistunenko, Dimitry A, Kurnikov, Igor V, Borisenko, Gregory G
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.09.2005
Subjects
Animals
Apoptosis - physiology
Cardiolipins - metabolism
Cytochrome
Cytochromes c - metabolism
HL-60 Cells
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Lymphoma
Mice
Mitochondria - metabolism
Mitochondrial Proteins - metabolism
Mortality
Oxidation
Oxidation-Reduction
Oxygenases - metabolism
Signal Transduction
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Summary:Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B-cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidation during apoptosis. The oxidation is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation.
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ISSN:1552-4450
1552-4469
DOI:10.1038/nchembio727