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Mitochondrial respiratory chain dysfunction, impaired intracellular Ca²⁺ homeostasis and activation of the mitochondrial apoptotic pathway are pathological hallmarks in animal and cellular models of familial amyotrophic lateral sclerosis associated with Cu/Zn‐superoxide dismutase mutations. Although intracellular Ca²⁺ homeostasis is thought to be intimately associated with mitochondrial functions, the temporal and causal correlation between mitochondrial Ca²⁺ uptake dysfunction and motor neuron death in familial amyotrophic lateral sclerosis remains to be established. We investigated mitochondrial Ca²⁺ handling in isolated brain, spinal cord and liver of mutant Cu/Zn‐superoxide dismutase transgenic mice at different disease stages. In G93A mutant transgenic mice, we found a significant decrease in mitochondrial Ca²⁺ loading capacity in brain and spinal cord, as compared with age‐matched controls, very …