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The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production

Title
The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production
Author
정미애
Keywords
Apoptosis; ROS; Mitochondria; Cytochrome c; Caspase; Bid
Issue Date
2017-11
Publisher
ELSEVIER SCIENCE INC
Citation
FREE RADICAL BIOLOGY AND MEDICINE, v. 112, page. 567-577
Abstract
Ligation of the death receptors for TNF-alpha, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the impairment of the mitochondrial respiratory chain. ROS generation was accompanied by caspase-8 activation, Bid cleavage, and cytochrome c release; it was blocked in FADD- and caspase-8-deficient cells, as well as by caspase-8 knockdown and inhibitor. Moreover, Bid knockdown abrogated TNF-alpha- or TRAIL-induced ROS generation, whereas overexpression of truncated Bid (tBid) or knockdown of cytochrome c spontaneously elevated ROS production. In addition, p53-overexpressing cells accumulated intracellular ROS via cytochrome c release mediated by the BH3-only protein Noxa induction. In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome c release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes. These data suggest that anti-apoptotic Bcl-2 proteins play an important role in mitochondrial ROS generation by preventing cytochrome c release. These data provide evidence that the FADD/caspase-8/Bid/cytochrome c axis is a crucial linker between death receptors and mitochondria, where they play a role in ROS generation and apoptosis.
URI
https://www.sciencedirect.com/science/article/pii/S0891584917307451?via%3Dihubhttp://repository.hanyang.ac.kr/handle/20.500.11754/116072
ISSN
0891-5849; 1873-4596
DOI
10.1016/j.freeradbiomed.2017.09.001
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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