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.

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