Mitochondrial glutathione: Importance and transport

Accumulating evidence pointing to mitochondria as critical participants in the control of apoptotic and necrotic cell death and in the development of specific disease states has led to a renaissance art the study of these org anelles. Because mitochondria are the major consumers of molecular oxygen w ithin cells, they stand as one of the most important generators of reactive oxygen species and therefore constitute potential targets of therapeutic i ntervention in pathologic states in which oxidative stress originates from these organelles. In this regard, mitochondria are specific targets of etha nol intoxication, thereby leading to reported morphologic and functional al terations of mitochondria. Because mitochondria are also indispensable for the maintenance of cell functions, their dysfunction induced by ethanol may be a key event in the development of alcoholic liver disease. Indeed, chro nic ethanol feeding in experimental animals has been reported to cause a se lective deficiency in the availability of reduced glutathione (GSH) in, mit ochondria due to the impaired functioning of the specific mitochondrial car rier that translocates GSH from cytosol into the mitochondrial matrix. Such a selective depletion sensitizes hepatocytes from chronic ethanol-fed anim als to the oxidative effects of cytokines, e.g., tumor necrosis factor (TNF ). Restoration of mitochondrial GSH by the in vivo administration of S-aden osyl-L-methionine or the in vitro use of GSH ethyl ester, prevents the susc eptibility of hepatocytes to TNF. Although the nature of this specific carr ier has not yet been uncovered, the elucidation of the mechanisms whereby e thanol leads to its impaired activity may provide important clues as to its function and mechanism of action, which in turn may be useful toward the d efinitive characterization and identification of this important carrier.