Mutations in cytochrome c oxidase subunit VIa cause metabolic and excitability defects in Drosophila
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Mitochondrial disorders have a multitude of causes and exhibit diverse symptoms. Dysfunction of cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial electron transport chain, is associated with several mitochondrial disorders. In this thesis, we characterized metabolic, contractile and excitability defects caused by a mutation in the Drosophila COX VIa gene (designated levy ), to understand the factors that contribute to COX-deficient mitochondrial disease. The levy mutants were isolated by their temperature-induced paralytic phenotype and exhibited severe COX deficiency. These mutants also showed severely altered respiration, which correlated temporally with reduced ATP levels on exposure to non-permissive temperature. The paralytic phenotype preceded alterations in respiration and ATP levels. Therefore, we investigated the cause of temperature-induced paralysis further. We demonstrate that neurons and muscles contributed autonomously to paralysis in levy 1 mutants. In addition, levy 1 mutants showed severe defects in contractile ability and muscle excitability. Muscle membranes were severely depolarized and action potential generation was affected upon exposure to non-permissive temperature. Furthermore, investigation of voltage-gated currents underlying muscle membrane excitability uncovered a specific, temperature-induced reduction in the amplitude of the L-type calcium channel current in the levy 1 mutant. These data provide evidence for the autonomous involvement of neurons and muscles, and a COX-mediated mechanism, which under conditions of temperature-induced stress reduces L-type calcium channel current, which may lead to the contractile dysfunction and paralytic behavior exhibited by levy 1 mutants.