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 on the study of these organelles. Because mitochondria are the major consumers of molecular oxygen within cells, they stand as one of the most important generators of reactive oxygen species and therefore constitute potential targets of therapeutic intervention in pathologic states in which oxidative stress originates from these organelles. In this regard, mitochondria are specific targets of ethanol intoxication, thereby leading to reported morphologic and functional alterations 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, chronic ethanol feeding in experimental animals has been reported to cause a selective deficiency in the availability of reduced glutathione (GSH) in mitochondria due to the impaired functioning of the specific mitochondrial carrier that translocates GSH from cytosol into the mitochondrial matrix. Such a selective depletion sensitizes hepatocytes from chronic ethanol-fed animals to the oxidative effects of cytokines, e.g., tumor necrosis factor (TNF). Restoration of mitochondrial GSH by the in vivo administration of S-adenosyl-L-methionine or the in vitro use of GSH ethyl ester prevents the susceptibility of hepatocytes to TNF. Although the nature of this specific carrier has not yet been uncovered, the elucidation of the mechanisms whereby ethanol 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 definitive characterization and identification of this important carrier.
Fernández-Checa
J C
JC
Department of Medicine, Hospital Clinic i Provincial and Instituto Investigaciones Biomédicas August Pi i Sunyer, Consejo Superior Investigaciones Científicas, Barcelona, Spain.
Kaplowitz
N
N
García-Ruiz
C
C
Colell
A
A
D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D000431:Ethanol / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D018384:Oxidative Stress
D000431:Ethanol; D005978:Glutathione