Madesh Muniswamy, Zong Wei-Xing, Hawkins Brian J, Ramasamy Subbiah, Venkatachalam Thilagavathi, Mukhopadhyay Partha, Doonan Patrick J, Irrinki Krishna M, Rajesh Mohanraj, Pacher Pál, Thompson Craig B
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA.
Mol Cell Biol. 2009 Jun;29(11):3099-112. doi: 10.1128/MCB.01845-08. Epub 2009 Mar 30.
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.
乙醇中毒会刺激促炎细胞因子的产生,增加活性氧的形成,并导致线粒体损伤。然而,关于乙醇诱导肝毒性的确切序列和成分的信息有限。急性乙醇暴露会增强线粒体超氧化物(O(2)(-))的产生,并损害线粒体对钙离子的处理能力。反过来,O(2)(-)会促进细胞色素c的释放和线粒体膜电位的丧失,这一过程不依赖于H(2)O(2)和二价阳离子,且以不依赖Bax的方式需要Bak参与。此外,触发Bak的促凋亡活性需要胞质中存在Bid,Bid是一种仅含BH3结构域的蛋白,由起始半胱天冬酶-2进行加工处理。这些研究共同确定了一条由O(2)(-)驱动、半胱天冬酶启动的凋亡途径,该途径选择性地涉及Bcl-2家族蛋白Bid和Bak。这条途径在老年动物长期摄入乙醇的过程中表现出来,并确定半胱天冬酶-2、Bid和Bak是O(2)(-)诱导凋亡的重要介质,可能成为开发治疗酒精性肝病疗法的有效靶点。