title: Execution of superoxide-induced cell death by the proapoptotic Bcl-2-related proteins Bid and Bak.
abstract: 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 (O(2)(*-)) production and impairs mitochondrial Ca(2+) handling. In turn, O(2)(*-) facilitates cytochrome c release and mitochondrial membrane potential loss that is not dependent upon H(2)O(2) 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 O(2)(*-)-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.
authors.affiliation: Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. madeshm@temple.edu
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