Fernández-Checa José C
Liver Unit, Instituto Malalties Digestives, Hospital Clinic i Provincial, Instituto Investigaciones Biomedicas August Pi i Sunyer, and Department of Experimental Pathology, Instituto Investigaciones Biomedicas Barcelona, Spain.
Ann Hepatol. 2003 Apr-Jun;2(2):69-75.
Reactive oxygen species (ROS) act as signaling intermediates regulating multiple cellular processes. The fate and disposal of the signaling species are determined by the actions of antioxidants, particularly glutathione (GSH). The mitochondrial pool of GSH (mGSH) arises from the transport of cytosol GSH by a specific mitochondrial carrier and is responsible for the maintenance of a healthy competent organelle. The depletion of mGSH upon impairment of the mitochondrial transport activity leaves mitochondria unprotected from damaging effects of ROS overgeneration within the mitochondrial electron transport chain. Tumor necrosis factor-alpha (TNF-alpha) has emerged as a key player in the progression of the alcohol-induced liver disease (ALD), and is known to target mitochondria. Key components of TNF signaling include sphingolipids, particularly ceramide generated from acidic sphingomyelinase activation serving as a source for gangliosides. In experimental models alcohol consumption enhances cholesterol levels and subsequent deposition into mitochondria resulting in selective decrease in the mGSH stores which is sufficient by itself to sensitize hepatocytes to TNF-alpha-mediated cell death. Thus, the combination of TNF-alpha overproduction, enhanced glycosphingolipid generation and selective mGSH depletion by alcohol intake cooperate making the liver sensitive to alcohol.
活性氧（ROS）作为调节多种细胞过程的信号中间体。信号分子的命运和处置由抗氧化剂，特别是谷胱甘肽（GSH）的作用决定。线粒体中的谷胱甘肽池（mGSH）来自于特定线粒体载体对胞质GSH的转运，负责维持健康的有功能的细胞器。线粒体转运活性受损时mGSH的耗竭使线粒体无法免受线粒体电子传递链中ROS过度产生的破坏作用。肿瘤坏死因子-α（TNF-α）已成为酒精性肝病（ALD）进展中的关键因素，并且已知其作用于线粒体。TNF信号传导的关键成分包括鞘脂，特别是由酸性鞘磷脂酶激活产生的神经酰胺，其作为神经节苷脂的来源。在实验模型中，饮酒会提高胆固醇水平并随后沉积到线粒体中，导致mGSH储备选择性减少，这本身就足以使肝细胞对TNF-α介导的细胞死亡敏感。因此，TNF-α的过度产生、糖鞘脂生成增加以及饮酒导致的选择性mGSH耗竭共同作用，使肝脏对酒精敏感。
