Mitochondrial glutathione: hepatocellular survival-death switch.
Steatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine-induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol-mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol-fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.
Garcia-Ruiz
Carmen
C
Liver Unit, Institute of Digestive Diseases, Hospital Clinic, Provincial, Barcelona, Spain.
Fernandez-Checa
José C
JC
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018450:Disease Progression; D000431:Ethanol / Q000494:pharmacology*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008560:Membrane Fluidity / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D005978:Glutathione