title: The effect of chronic alcohol consumption on mitochondrial calcium handling in hepatocytes.
abstract: The damage to liver mitochondria is universally observed in both humans and animal models after excessive alcohol consumption. Acute alcohol treatment has been shown to stimulate calcium (Ca2+) release from internal stores in hepatocytes. The resultant increase in cytosolic Ca2+is expected to be accumulated by neighboring mitochondria, which could potentially lead to mitochondrial Ca2+overload and injury. Our data indicate that total and free mitochondrial matrix Ca2+levels are, indeed, elevated in hepatocytes isolated from alcohol-fed rats compared with their pair-fed control littermates. In permeabilized hepatocytes, the rates of mitochondrial Ca2+uptake were substantially increased after chronic alcohol feeding, whereas those of mitochondrial Ca2+efflux were decreased. The changes in mitochondrial Ca2+handling could be explained by an up-regulation of the mitochondrial Ca2+uniporter and loss of a cyclosporin A-sensitive Ca2+transport pathway. In intact cells, hormone-induced increases in mitochondrial Ca2+declined at slower rates leading to more prolonged elevations of matrix Ca2+in the alcohol-fed group compared with controls. Moreover, treatment with submaximal concentrations of Ca2+-mobilizing hormones markedly increased the levels of mitochondrial reactive oxygen species (ROS) in hepatocytes from alcohol-fed rats, but did not affect ROS levels in controls. The changes in mitochondrial Ca2+handling are expected to buffer and attenuate cytosolic Ca2+increases induced by acute alcohol exposure or hormone stimulation. However, these alterations in mitochondrial Ca2+handling may also lead to Ca2+overload during cytosolic Ca2+increases, which may stimulate the production of mitochondrial ROS, and thus contribute to alcohol-induced liver injury.
authors: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors: Guoqiang
authors: G
authors: Wang
authors: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors: Elisabeth
authors: E
authors: Mémin
authors: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors: Ishwarya
authors: I
authors: Murali
authors: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors: Lawrence D
authors: LD
authors: Gaspers
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D014280:Triglycerides; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: alcohol; mitochondria; mitochondrial calcium homeostasis; mitochondrial calcium uniporter; reactive oxygen species