Execution of superoxide-induced cell death by the proapoptotic Bcl-2-related proteins Bid and Bak

Muniswamy Madesh, Wei Xing Zong, Brian J. Hawkins, Subbiah Ramasamy, Thilagavathi Venkatachalam, Partha Mukhopadhyay, Patrick J. Doonan, Krishna M. Irrinki, Mohanraj Rajesh, Pál Pacher, Craig B. Thompson

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


Ethanol intoxication stimulates the production of proinflammatory cytokines, increases the formation of reactive oxygen species, and induces mitochondrial impairment. However, information is limited as to the exact sequence and components involved in ethanol-induced hepatotoxicity. Acute ethanol exposure enhances mitochondrial superoxide (O2.-) production and impairs mitochondrial Ca2+ handling. In turn, O 2.- facilitates cytochrome c release and mitochondrial membrane potential loss that is not dependent upon H2O2 and divalent cations and requires Bak in a Bax-independent fashion. Furthermore, triggering of Bak's proapoptotic activity requires the cytosolic presence of Bid, a BH3-only protein that is processed by the initiator caspase-2. Together, these studies identify an O2.--driven, caspase-initiated apoptotic pathway that selectively involves the Bcl-2 family proteins Bid and Bak. This pathway manifests itself during chronic ethanol consumption in aged animals and identifies caspase-2, Bid, and Bak as essential mediators of O 2.--induced apoptosis that may prove effective targets for the development of therapeutics to treat alcoholic liver disease.

Original languageEnglish
Pages (from-to)3099-3112
Number of pages14
JournalMolecular and Cellular Biology
Issue number11
Publication statusPublished - Jun 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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