Neural mitochondrial Ca²⁺ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice

Mitochondrial respiratory chain dysfunction, impaired intracellular Ca ²⁺ 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 early on in the course of the disease, long before the onset of motor weakness and massive neuronal death. Ca ²⁺ loading capacity was not significantly changed in liver G93A mitochondria. We also confirmed Ca²⁺ capacity impairment in spinal cord mitochondria from a different line of mice expressing G85R mutant Cu/Zn-superoxide dismutase. In excitable cells, such as motor neurons, mitochondria play an important role in handling rapid cytosolic Ca²⁺ transients. Thus, mitochondrial dysfunction and Ca²⁺-mediated excitotoxicity are likely to be interconnected mechanisms that contribute to neuronal degeneration in familial amyotrophic lateral sclerosis.