Mitochondrial function in liver disease.
Oxidative stress is involved in the pathogenesis and progression of different liver diseases, such as alcoholic liver disease and biliary cirrhosis. The increased mitochondrial production of O2(-) at complexes I and III, and consequently of H2O2 and other reactive oxygen species (ROS), triggered by NADH overproduction seems the major cause of mitochondrial and cellular oxidative stress and damage in chronic alcoholism. The mitochondrial oxidative stress renders hepatocytes susceptible to ethanol- or acetaldehyde-induced mitochondrial membrane permeability transition (MMPT) and apoptosis. Nitrosative stress contributes to cell death by peroxynitrite formation. The expression of the death receptor ligand CD95 is also up-regulated by acetaldehyde metabolism. Consequently, a dual mechanism, NADH-driven MMPT and CD95-mediated apoptosis, involving in both cases acetaldehyde metabolism and ROS production, operates in ethanol-induced apoptosis. In the biliary cirrhosis induced by chronic cholestasis, liver mitochondria show increased H2O2 production and GSH depletion and oxidation. Dysfunctional hepatocytes, with a loss in mitochondrial cardiolipin and decreased mitochondrial membrane potential evolve during cholestasis to apoptosis. Ursodeoxycholic acid prevents enlargement of this population as well as mitochondrial oxidative stress. Mitochondrial oxidative stress precedes the initiation and execution of hepatocyte apoptosis in chronic alcoholism and biliary cirrhosis. We suggest that overproduction of mitochondrial NADH is the primary cause for the development of alcoholic and non-alcoholic liver disease by a situation of chronic mitochondrial oxidative stress, which should be considered the second hit that renders hepatocytes susceptible to cell injury and apoptosis.
Sastre
Juan
J
Dept.of Physiology, School of Medicine, University of Valencia, Spain. juan.sastre@uv.es
Serviddio
Gaetano
G
Pereda
Javier
J
Minana
Juan B
JB
Arduini
Alessandro
A
Vendemiale
Gianluigi
G
Poli
Giuseppe
G
Pallardo
Federico V
FV
Vina
Jose
J
D000818:Animals; D017209:Apoptosis; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats
D009243:NAD