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Mutations in mitochondrial DNA (mtDNA) were long thought to range from neutral to deleterious, but not beneficial. However, the maintenance of mitochondrial variation within species indicates a possible selective advantage conferred by favourable mtDNA mutations. I hypothesised that mtDNA variation may be maintained through interactions of mtDNA with environmental factors, including diet, temperature and the presence of stressors. I further hypothesised that experimentally manipulating the interactions of mtDNA and environmental factors may allow context specific favourable mutations in mtDNA to be discovered. Diet provides a strong environmental factor to identify favourable mtDNA mutations as the macronutrients of diet provide substrate to the mitochondria at different stages of the electron transport system to produce cellular energy. Thus modulating diet and other environmental factors may elucidate favourable mutations as these mutations may be context dependent, being favourable in one context, but deleterious in another. The overall goal of this thesis is to determine whether a single mtDNA mutation can have favourable effects on organismal fitness and health through interactions with environmental factors. I utilise the model organism Drosophila melanogaster to investigate the selective advantage of mtDNA and attempt to identify a favourable mutation. The D. melanogaster lines I utilise have a constant nuclear DNA background but differ by known mtDNA mutations. This thesis is composed of five experimental chapters. Chapters 2, 3 and 4 focus on identifying a selective advantage of an mtDNA haplotype primarily through diet by mitotype interactions and determining a specific mutation that drives a selective advantage. Chapters 5 and 6 then utilise the knowledge gained in the previous chapters to generalise the response to adult longevity and response to environmental stressors. My work here has resulted in two major conclusions. First a single mtDNA mutation can provide a selective fitness advantage and benefit organismal health and second, mitotype specific favourable responses are context dependent.