Incompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signalling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter response to redox stress induced by N-acetyl cysteine (NAC). We studied three Drosophila melanogaster lines with mitochondrial genomes 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 fluorespirometry, we show that NAC did not alter H 2 O 2 flux but suppressed complex I-linked respiration in female flies, maintaining a reduced glutathione pool. High mortality in BAR females was associated with severe suppression of complex I-linked respiration, rising H 2 O 2 flux in ovaries and oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by suppression of complex-I linked respiration, to the point of death in some mitonuclear lines.