Redox stress shortens lifespan through suppression of respiratory complex I in flies with mitonuclear incompatibilities.

Incompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signaling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter the physiological response to redox stress induced by N-acetyl cysteine (NAC). We studied three Drosophila melanogaster lines with mitochondrial genomes that were either coevolved (WT) or mildly mismatched (BAR, COX) to an isogenic nuclear background. Responses to NAC varied substantially with mitonuclear genotype, sex, tissue and dose. NAC caused infertility and high mortality in some groups, but not others. Using tissue-specific high-resolution fluorespirometry, we show that NAC did not alter HO flux but suppressed complex I-linked respiration in female flies, while maintaining a reduced glutathione pool. The high mortality in BAR females was associated with severe (>50 %) suppression of complex I-linked respiration, rising HO flux in the ovaries, and significant oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by the suppression of complex-I linked respiration, to the point of death in some mitonuclear lines. We propose that suppression of complex I-linked respiration is a general mechanism to maintain redox homeostasis in tissues, which could offset oxidative stress in ageing, producing a metabolic phenotype linked with epigenetic changes and age-related decline.