Redox regulation and signaling lipids in mitochondrial apoptosis.
Apoptosis can be regulated at multiple levels. A number of proteins with regulatory function in cell death are sensitive to cellular redox environment. The antioxidant glutathione (GSH) and redox-sensitive proteins, thioredoxin and glutathione S-transferase, thus regulate cell death pathways by modulating the redox state of specific thiol residues of target proteins including stress kinases, transcription factors, and caspases. GSH in mitochondria plays an important role in the integrity of mitochondrial proteins and lipids known to play a vital role in the permeabilization of mitochondrial membranes and release of proapoptotic factors. The regulation of mitochondrial GSH (mGSH) is determined by its uptake from the cytosol which is dependent on appropriate membrane dynamics. The deposition of cholesterol in mitochondria induced by alcohol intake impairs this translocation, resulting in severe depletion of mGSH and in sensitization to apoptosis stimuli. Although the interaction of proapoptotic proteins with mitochondria initiates apoptotic pathways, recent data indicate that the mitochondrial trafficking of glycosphingolipids, e.g., ganglioside GD3, induced by apoptotic stimuli is a key event that sets off mitochondrial-dependent apoptotic cascades.
Fernández-Checa
José C
JC
Liver Unit, Instituto Malalties Digestives, Hospital Clinic i Provincial, Instituto Investigaciones Biomedicas August Pi I Sunyer, Consejo Superior Investigaciones Científicas, 08036 Barcelona, Spain. checa@medicina.ub.es
D017209:Apoptosis; D002784:Cholesterol / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D008055:Lipids / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000502:physiology
D008055:Lipids; D017382:Reactive Oxygen Species; D013107:Sphingolipids; D002784:Cholesterol; D005978:Glutathione