Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax

Tae Hyoung Kim, Yongge Zhao, Michael J. Barber, Diane K. Kuharsky, Xiao-Ming Yin

Research output: Contribution to journalArticle

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Abstract

Bid, a pro-apoptosis "BH3-only" member of the Bcl-2 family, can be cleaved by caspase-8 after Fas/TNF-R1 engagement. The p15 form of truncated Bid (tBid) translocates to mitochondria and induces cytochrome c release, leading to the activation of downstream caspases and apoptosis. In the current study, we investigated the mechanism by which tBid regulated cytochrome c release in terms of its relationship to mitochondrial permeability transition and Bax, another Bcl-2 family protein. We employed an in vitro reconstitution system as well as cell cultures and an animal model to reflect the physiological environment where Bid could be functional. We found that induction of cytochrome c release by tBid was not accompanied by a permeability transition even at high doses. Indeed, inhibition of permeability transition did not suppress the activity of tBid in vitro nor could they block Fas activation-induced, Bid-dependent hepatocyte apoptosis in cultures. Furthermore, Mg2+, although inhibiting permeability transition, actually enhanced the ability of tBid to induce cytochrome c release. We also found that tBid did not require Bax to induce cytochrome c release in vitro. In addition, mice deficient in bax were still highly susceptible to anti-Fas-induced hepatocyte apoptosis, in which cytochrome c release was unaffected. Moreover, although Bax-induced cytochrome c release was not dependent on tBid, the two proteins could function synergistically. We conclude that Bid possesses the biochemical activity to induce cytochrome c release through a mechanism independent of mitochondrial permeability transition pore and Bax.

Original languageEnglish (US)
Pages (from-to)39474-39481
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number50
DOIs
StatePublished - Dec 15 2000
Externally publishedYes

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Cytochromes c
Permeability
Apoptosis
Hepatocytes
BH3 Interacting Domain Death Agonist Protein
Chemical activation
Mitochondria
mitochondrial permeability transition pore
Caspase 8
Caspases
Cell culture
Animals
Proteins
Animal Models
Cell Culture Techniques
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. / Kim, Tae Hyoung; Zhao, Yongge; Barber, Michael J.; Kuharsky, Diane K.; Yin, Xiao-Ming.

In: Journal of Biological Chemistry, Vol. 275, No. 50, 15.12.2000, p. 39474-39481.

Research output: Contribution to journalArticle

Kim, Tae Hyoung ; Zhao, Yongge ; Barber, Michael J. ; Kuharsky, Diane K. ; Yin, Xiao-Ming. / Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 50. pp. 39474-39481.
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