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

Wan Sung Kim, Kwang Soon Lee, Ji Hee Kim, Chun Ki Kim, Gwangsoo Lee, Jongseon Choe, Moo Ho Won, Tae Hyoung Kim, Dooil Jeoung, Hansoo Lee, Ji Yoon Kim, Mi Ae Jeong, Kwon Soo Ha, Young Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)


Ligation of the death receptors for TNF-α, 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-α- 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.

Original languageEnglish
Pages (from-to)567-577
Number of pages11
JournalFree Radical Biology and Medicine
Publication statusPublished - 2017 Nov

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)


Dive into the research topics of 'The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production'. Together they form a unique fingerprint.

Cite this