Journal
NATURE CHEMICAL BIOLOGY
Volume 1, Issue 4, Pages 223-232Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio727
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Funding
- NHLBI NIH HHS [1R01 HL70755, P01 HL070807] Funding Source: Medline
- NIOSH CDC HHS [1R01 OH008282] Funding Source: Medline
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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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