Abstract

Mitochondrial function depends on direct interactions between respiratory proteins encoded by genes in two genomes, mitochondrial and nuclear, which evolve in very different ways. Serious incompatibilities between these genomes can have severe effects on development, fitness and viability. The effect of subtle mitonuclear mismatches has received less attention, especially when subject to mild physiological stress, such as high-protein diet, though these subtle mismatches are arguably more relevant to both evolutionary population dynamics and precision medicine. Here we show that subtle differences in mtDNA (1-9 SNPs) between Drosophila melanogaster lines that are isogenic in their nuclear background can cause substantial differences in lifespan, fertility and physical activity. These phenotypic differences were amplified by a high protein diet.

Even though the genotypic differences between our fly lines affect respiratory-chain function alone, we only detected subtle variations in substrate use and complex I function using high-resolution O2k fluorespirometry in the thoraces and reproductive tissues of young and old flies of both sexes. These subtle variations underpinned marked differences at the level of metabolic flux and especially gene expression, with changes in core metabolism including Krebs cycle and glycolysis as well as purine and pyrimidine pathways.

Differences in gene expression were especially marked in the reproductive tissues of both sexes, and in older flies. Surprisingly, the line with the most mitonuclear mismatches also had (slightly) the best complex I function in young adults, which corresponded to the longest lifespan, the greatest fertility and the most physical activity. This suggests that subtle differences in substrate preference can have concerted effects on metabolic plasticity, gene expression and epigenetic state. Better complex I function may enhance metabolic plasticity and life-history outcomes. These outcomes are not easily predicted on the basis of mitonuclear match alone, but a better understanding of respiratory flux will have important implications for both evolutionary biology and health.