Ca(2+) rise within a narrow window of concentration prevents functional injury of mitochondria exposed to hypoxia/reoxygenation by increasing antioxidative defence

Injury of liver by ischaemia crucially involves mitochondrial damage. The role of Ca(2+) in mitochondrial damage is still unclear. We investigated the effect of low micromolar Ca(2+) concentrations on respiration, membrane permeability, and antioxidative defence in liver mitochondria exposed to hypoxia/reoxygenation. Hypoxia/reoxygenation caused decrease in state 3 respiration and in the respiratory control ratio. Liver mitochondria were almost completely protected at about 2 microM Ca(2+). Below and above 2 microM Ca(2+), mitochondrial function was deteriorated, as indicated by the decrease in respiratory control ratio. Above 2 microM Ca(2+), the mitochondrial membrane was permeabilized, as demonstrated by the sensitivity of state 3 respiration to NADH. Below 2 microM Ca(2+), the nitric oxide synthase inhibitor nitro-l-arginine methylester had a protective effect. The activities of the manganese superoxide dismutase and glutathione peroxidase after hypoxia showed maximal values at about 2 microM Ca(2+). We conclude that Ca(2+) exerts a protective effect on mitochondria within a narrow concentration window, by increasing the antioxidative defence.