Two Genomes, One Metabolome: Mitonuclear Incompatibility Remodels Developmental Metabolism and Fitness in Drosophila
- 1University of South Dakota
Abstract
Mitochondrial-nuclear (hereafter mitonuclear) genetic variation can alter cellular bioenergetics and metabolism via jointly encoding the subunits of oxidative phosphorylation (OXPHOS) system. Here we tested whether genetic variation in biochemical and bioenergetic phenotype can scale up across higher levels of biological organization to affect organismal development. We used a panel of (mtDNA); nDNA genotypes created by asymmetric substitution of divergent mtDNA between Drosophila melanogaster and its sister species D. simulans. Two genotypes (ore); OreR and (ore); Aut carry coevolved mitonuclear genomes from D. melanogaster, whereas the other two (w501); Aut and (w501); OreR harbor D. simulans mitochondrial DNA introgressed onto D. melanogaster nuclear backgrounds. We utilized untargeted metabolomics to track down the comprehensive biochemical footprint of the joint genomic architecture in the metabolome of these genotypes. We show that in (w501); OreR larvae with mitonuclear genome incompatibility there is extensive and coordinated metabolic remodeling of carbon, nitrogen, and redox balance, characterized by increased glycolysis, limited TCA cycle, amino acid scarcity, reduced nucleic acid balance, lipid remodeling, with compensatory activation of antioxidant pathways. This biochemical rewiring puts a physiological constraint that prioritizes maintenance metabolism over larval growth, leading to reduced body size, slow locomotion and delayed development, despite a compensatory increase in feeding in these larvae. These findings underscore the context dependency of mitonuclear interactions, which can uniquely scale up to influence organismal energy budget trade-offs, fitness and life-history evolution.
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BibTeX
@misc{singh2026genomes,
title = {{Two Genomes, One Metabolome: Mitonuclear Incompatibility Remodels Developmental Metabolism and Fitness in Drosophila}},
author = {A. Singh and B. Frias and B. M. Deaver and A. C. Edwards and J. K. Cambara and O. B. Matoo},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.29.728848},
url = {https://www.biorxiv.org/content/10.64898/2026.05.29.728848v2},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Two Genomes, One Metabolome: Mitonuclear Incompatibility Remodels Developmental Metabolism and Fitness in Drosophila
AU - A. Singh
AU - B. Frias
AU - B. M. Deaver
AU - A. C. Edwards
AU - J. K. Cambara
AU - O. B. Matoo
PY - 2026
DA - 2026/05/29
PB - bioRxiv
DO - 10.64898/2026.05.29.728848
UR - https://www.biorxiv.org/content/10.64898/2026.05.29.728848v2
AB - Mitochondrial-nuclear (hereafter mitonuclear) genetic variation can alter cellular bioenergetics and metabolism via jointly encoding the subunits of oxidative phosphorylation (OXPHOS) system. Here we tested whether genetic variation in biochemical and bioenergetic phenotype can scale up across higher levels of biological organization to affect organismal development. We used a panel of (mtDNA); nDNA genotypes created by asymmetric substitution of divergent mtDNA between Drosophila melanogaster and its sister species D. simulans. Two genotypes (ore); OreR and (ore); Aut carry coevolved mitonuclear genomes from D. melanogaster, whereas the other two (w501); Aut and (w501); OreR harbor D. simulans mitochondrial DNA introgressed onto D. melanogaster nuclear backgrounds. We utilized untargeted metabolomics to track down the comprehensive biochemical footprint of the joint genomic architecture in the metabolome of these genotypes. We show that in (w501); OreR larvae with mitonuclear genome incompatibility there is extensive and coordinated metabolic remodeling of carbon, nitrogen, and redox balance, characterized by increased glycolysis, limited TCA cycle, amino acid scarcity, reduced nucleic acid balance, lipid remodeling, with compensatory activation of antioxidant pathways. This biochemical rewiring puts a physiological constraint that prioritizes maintenance metabolism over larval growth, leading to reduced body size, slow locomotion and delayed development, despite a compensatory increase in feeding in these larvae. These findings underscore the context dependency of mitonuclear interactions, which can uniquely scale up to influence organismal energy budget trade-offs, fitness and life-history evolution.
ER -