title: Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.
abstract: 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.
authors.affiliation: Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. vkagan@eoh.pitt.edu
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.forename: Jianfei
authors.initials: J
authors.lastname: Jiang
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Ritov
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Amoscato
authors.forename: Anatoly N
authors.initials: AN
authors.lastname: Osipov
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Belikova
authors.forename: Alexandr A
authors.initials: AA
authors.lastname: Kapralov
authors.forename: Vidisha
authors.initials: V
authors.lastname: Kini
authors.forename: Irina I
authors.initials: II
authors.lastname: Vlasova
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Meimei
authors.initials: M
authors.lastname: Zou
authors.forename: Peter
authors.initials: P
authors.lastname: Di
authors.forename: Dimitry A
authors.initials: DA
authors.lastname: Svistunenko
authors.forename: Igor V
authors.initials: IV
authors.lastname: Kurnikov
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Borisenko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002308:Cardiolipins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D002308:Cardiolipins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D010105:Oxygenases