Source data Fig 1E.

Nutrition is a primary determinant of health, but responses to nutrition vary with genotype. Epistasis between mitochondrial and nuclear genomes may cause some of this variation, but which mitochondrial loci and nutrients participate in complex gene-by-gene-by-diet interactions? Furthermore, it remains unknown whether mitonuclear epistasis is involved only in the immediate responses to changes in diet, or whether mitonuclear genotype might modulate sensitivity to variation in parental nutrition, to shape intergenerational fitness responses. Here, in Drosophila melanogaster, we show that mitonuclear epistasis shapes fitness responses to variation in dietary lipids and amino acids. We also show that mitonuclear genotype modulates the parental effect of dietary lipid and amino acid variation on offspring fitness. Effect sizes for the interactions between diet, mitogenotype, and nucleogenotype were equal to or greater than the main effect of diet for some traits, suggesting that dietary impacts cannot be understood without first accounting for these interactions. Associating phenotype to mtDNA variation in a subset of populations implicated a C/T polymorphism in mt:lrRNA, which encodes the 16S rRNA of the mitochondrial ribosome. This association suggests that directionally different responses to dietary changes can result from variants on mtDNA that do not change protein coding sequence, dependent on epistatic interactions with variation in the nuclear genome.营养是健康的核心决定因素，但机体对营养的响应随基因型而异。线粒体与核基因组间的上位性（epistasis）可能是这种差异的部分成因，但究竟哪些线粒体基因座与营养物质参与了复杂的基因-基因-膳食互作呢？此外，目前尚不清楚线粒体核上位性是否仅参与膳食变化的即时响应，抑或线粒体核基因型是否可通过调控亲本营养变化的敏感性，进而塑造跨代适合度（fitness）响应。本研究以黑腹果蝇（Drosophila melanogaster）为模型，证实线粒体核上位性可调控膳食脂质与氨基酸变化所引发的适合度响应。本研究同时发现，线粒体核基因型可调控膳食脂质与氨基酸变异对后代适合度的亲本效应。针对部分性状而言，膳食、线粒体基因型（mitogenotype）与核基因型（nucleogenotype）三者间互作的效应量等于甚至大于膳食的主效应，这表明若不先厘清这些互作关系，便无法完整理解膳食的生理影响。通过对部分种群的表型与线粒体DNA（mtDNA）变异进行关联分析，本研究锁定了mt:lrRNA基因中的C/T多态性——该基因编码线粒体核糖体的16S rRNA。这一关联结果表明，膳食变化的定向响应差异可由不改变蛋白质编码序列的线粒体DNA变异引发，此类变异的效应依赖于与核基因组变异间的上位性互作。