Mitochondrial genotype alters the impact of rapamycin on the transcriptional response to nutrients in Drosophila

BackgroundIn addition to their well characterized role in cellular energy production, new evidence has revealed the involvement of mitochondria in diverse signaling pathways that regulate a broad array of cellular functions. The mitochondrial genome (mtDNA) encodes essential components of the oxidative phosphorylation (OXPHOS) pathway whose expression must be coordinated with the components transcribed from the nuclear genome. Mitochondrial dysfunction is associated with disorders including cancer and neurodegenerative diseases, yet the role of the complex interactions between the mitochondrial and nuclear genomes are poorly understood.ResultsUsing a Drosophila model in which alternative mtDNAs are present on a common nuclear background, we studied the effects of this altered mitonuclear communication on the transcriptomic response to altered nutrient status. Adult flies with the 'native' and 'disrupted' genotypes were re-fed following brief starvation, with or without exposure to rapamycin, the cognate inhibitor of the nutrient-sensing target of rapamycin (TOR). RNAseq showed that alternative mtDNA genotypes affect the temporal transcriptional response to nutrients in a rapamycin-dependent manner. Pathways most greatly affected were OXPHOS, protein metabolism and fatty acid metabolism. A distinct set of testis-specific genes was also differentially regulated in the experiment.ConclusionsMany of the differentially expressed genes between alternative mitonuclear genotypes have no direct interaction with mtDNA gene products, suggesting that the mtDNA genotype contributes to retrograde signaling from mitochondria to the nucleus. The interaction of mitochondrial genotype (mtDNA) with rapamycin treatment identifies new links between mitochondria and the nutrient-sensing mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway.

Automated summary

The mitochondria not only play a crucial role in cellular energy production but also participate in regulating various signaling pathways that impact cellular functions. Mitochondrial dysfunction is associated with disorders like cancer and neurodegenerative diseases, underscoring the importance of understanding the interactions between mitochondrial and nuclear genomes. In a Drosophila model, it was found that different mitochondrial DNA genotypes influence the temporal transcriptional response to nutrients, especially in a rapamycin-dependent manner, affecting pathways related to oxidative phosphorylation, protein metabolism, and fatty acid metabolism. The study also identified specific genes in the testis that were differentially regulated based on mitochondrial genotype, highlighting the impact of mitochondrial retrograde signaling on nuclear gene expression. Additionally, the interaction between mitochondrial genotype and rapamycin treatment revealed new connections between mitochondria and the nutrient-sensing mTORC1 signaling pathway.