Animals vary genetically in responses to dietary change. Both mitochondrial and nuclear genomes contribute to this variation, but the role of combinatorial "mito-nuclear" genetic variation is understudied. We do not know whether specific nutrients modify patterns of mito-nuclear variation, nor whether putative epigenetic mechanisms play a role. Here, we show that enriching dietary essential amino acids or lipids modifies patterns of mito-nuclear variation in Drosophila life-history, including transgenerational effects of lipids. Systematically evaluating alternative statistical models revealed that diet-mito-nuclear interactions were a leading driver of phenotypic variation. Mito-nuclear genotype repeatably predicted phenotypic impacts of nutritional changes, but genotypes bearing naturally co-occurring pairs of mitochondria and nuclei did not necessarily outperform novel pairings, suggesting that nutrition-dependent phenotypes cannot easily be optimised by matching mitochondria to coincident nuclear genotypes. These results enhance understanding of how nutrition and genetics sculpt phenotype, with potential implications for human mitochondrial transfer therapies.

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