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 journalArticle

11 Citations (Scopus)

Abstract

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
Volume112
DOIs
StatePublished - 2017 Nov 1

Fingerprint

Death Domain Receptors
Caspase 8
Cytochromes c
Reactive Oxygen Species
Noxae
Apoptosis
Mitochondria
Caspase Inhibitors
Lipoxygenase
Cell-Free System
Xanthine Oxidase
NADPH Oxidase
Prostaglandin-Endoperoxide Synthases
Caspases
Electron Transport
Ligation
Proteins
Antioxidants
Chemical activation

Keywords

  • Apoptosis
  • Bid
  • Caspase
  • Cytochrome c
  • Mitochondria
  • ROS

Cite this

Kim, Wan Sung ; Lee, Kwang Soon ; Kim, Ji Hee ; Kim, Chun Ki ; Lee, Gwangsoo ; Choe, Jongseon ; Won, Moo Ho ; Kim, Tae Hyoung ; Jeoung, Dooil ; Lee, Hansoo ; Kim, Ji Yoon ; Jeong, Mi Ae ; Ha, Kwon Soo ; Kwon, Young Guen ; Kim, Young Myeong. / The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production. In: Free Radical Biology and Medicine. 2017 ; Vol. 112. pp. 567-577.
@article{6f7ef0b19f8c4f729417cb1a0948840d,
title = "The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production",
abstract = "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.",
keywords = "Apoptosis, Bid, Caspase, Cytochrome c, Mitochondria, ROS",
author = "Kim, {Wan Sung} and Lee, {Kwang Soon} and Kim, {Ji Hee} and Kim, {Chun Ki} and Gwangsoo Lee and Jongseon Choe and Won, {Moo Ho} and Kim, {Tae Hyoung} and Dooil Jeoung and Hansoo Lee and Kim, {Ji Yoon} and Jeong, {Mi Ae} and Ha, {Kwon Soo} and Kwon, {Young Guen} and Kim, {Young Myeong}",
year = "2017",
month = "11",
day = "1",
doi = "10.1016/j.freeradbiomed.2017.09.001",
language = "English",
volume = "112",
pages = "567--577",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",

}

Kim, WS, Lee, KS, Kim, JH, Kim, CK, Lee, G, Choe, J, Won, MH, Kim, TH, Jeoung, D, Lee, H, Kim, JY, Jeong, MA, Ha, KS, Kwon, YG & Kim, YM 2017, 'The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production', Free Radical Biology and Medicine, vol. 112, pp. 567-577. https://doi.org/10.1016/j.freeradbiomed.2017.09.001

The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production. / Kim, Wan Sung; Lee, Kwang Soon; Kim, Ji Hee; Kim, Chun Ki; Lee, Gwangsoo; Choe, Jongseon; Won, Moo Ho; Kim, Tae Hyoung; Jeoung, Dooil; Lee, Hansoo; Kim, Ji Yoon; Jeong, Mi Ae; Ha, Kwon Soo; Kwon, Young Guen; Kim, Young Myeong.

In: Free Radical Biology and Medicine, Vol. 112, 01.11.2017, p. 567-577.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production

AU - Kim, Wan Sung

AU - Lee, Kwang Soon

AU - Kim, Ji Hee

AU - Kim, Chun Ki

AU - Lee, Gwangsoo

AU - Choe, Jongseon

AU - Won, Moo Ho

AU - Kim, Tae Hyoung

AU - Jeoung, Dooil

AU - Lee, Hansoo

AU - Kim, Ji Yoon

AU - Jeong, Mi Ae

AU - Ha, Kwon Soo

AU - Kwon, Young Guen

AU - Kim, Young Myeong

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Bid

KW - Caspase

KW - Cytochrome c

KW - Mitochondria

KW - ROS

UR - http://www.scopus.com/inward/record.url?scp=85028966927&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2017.09.001

DO - 10.1016/j.freeradbiomed.2017.09.001

M3 - Article

C2 - 28888620

AN - SCOPUS:85028966927

VL - 112

SP - 567

EP - 577

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -