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Mitochondrial encephalomyopathies are disturbingly complex and devastating diseases, reflecting the underlying importance of the affected organelle. Therapeutic approaches for these diseases remain limited due to a poor understanding of disease pathogenesis resulting largely from a lack of tractable model systems in which to study these diseases. This is especially so for disease conditions resulting from mutations directly affecting the mitochondrial genome. Recent studies using Drosophila to develop genetic models with endogenous mitochondrial mutations suggest the fruit fly will contribute significantly to our understanding of mitochondrial disease pathogenesis and the development of novel therapeutic avenues.