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
Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Nat Chem Biol. 2005 Sep;1(4):223-32. doi: 10.1038/nchembio727. Epub 2005 Aug 14.
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.
程序性死亡（凋亡）在受损或不需要的细胞中被开启，以确保它们能够进行干净且安全的自我清除。最初的凋亡事件在线粒体中协调进行，在此过程中，包括细胞色素c在内的几种促凋亡因子被释放到细胞质中，以触发半胱天冬酶级联反应。释放机制包括B细胞/淋巴瘤2家族蛋白与线粒体特异性磷脂心磷脂相互作用，导致线粒体外膜通透性增加。通过氧化脂质组学，我们发现心磷脂是线粒体中唯一在凋亡过程中发生早期氧化的磷脂。这种氧化由与心磷脂结合的细胞色素c的心磷脂特异性过氧化物酶活性催化。在凋亡过程中一个先前未被描述的步骤中，我们发现氧化的心磷脂是促凋亡因子释放所必需的。这些结果为活性氧在触发细胞死亡途径中的作用提供了见解，并描述了细胞色素c在半胱天冬酶激活之前的早期作用。
