A38 Mitochondrial interventions rescue disease phenotypes in a drosophila model of huntington’s disease

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BackgroundMetabolic dysfunction is a hallmark of HD pathology. Decreased glucose metabolism and increased lactate concentrations in HD brains suggest mitochondrial involvement in the disease. Moreover, alterations in mitochondrial fission/fusion balance have also been reported in several HD models, with repercussions on the ability of cells to clear damaged mitochondria.AimsHere we employ a Drosophila model of HD to study mitochondrial and neuronal dysfunction. We investigate the overexpression of Parkin, an E3 ubiquitin ligase involved in mitochondrial fission/fusion and quality control, as well as the expression of an alternative oxidase (AOX) which bypasses the activity of the respiratory complexes III and IV.MethodsHigh resolution respirometry was performed with an Oroboros O2K Oxygraph which permitted measurement of mitochondrial leak, oxidative phosphorylation (oxphos) capacity, electron transfer system capacity and cytochrome C loss. Mitochondrial shape and mass were assessed by electron microscopy and citrate synthase activity. Neuronal phenotypes were studied by measuring the loss of eye rhabdomeres, deficits in eclosion from the pupal case and the longevity of adult flies.ResultsOverexpression of Parkin in HD muscles significantly improved mitochondrial function by reducing mitochondrial leak, increasing the oxphos and electron transfer system capacity of Complex I and I+II, and reducing cytochrome C loss. Moreover Parkin overexpression increased mitochondrial fission and autophagy. All neuronally associated defects were robustly rescued by coexpression of Parkin in HD flies. Bypassing mitochondrial defects of complex III and IV via AOX also resulted in amelioration of all neuronal phenotypes and provided a striking rescue of shortened lifespan in HD flies.ConclusionsThis study highlights the likely contribution of mitochondrial dysfunction to HD and the importance of improving mitochondrial function and quality as a potential therapeutic intervention.

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