Novel conplastic strains reveal direct and independent effects of mitochondrial genomic variants on intrinsic aerobic fitness

Abstract

Due to lack of appropriate animal models, the potential contributions of inherited mitochondrial genomic factors to complex traits are less well studied compared to inherited nuclear genomic factors. To unambiguously quantify the effect of the inherited mitochondrial factors on aerobic fitness and cardiovascular disease, we developed and characterized novel reciprocal conplastic strains by substitution of different mitochondrial genomes (mtDNA) on the same nuclear genetic background permissive to the development of cardiovascular disease. Conplastic strains of the Dahl S rat nuclear genomes with mtDNA from the Spontaneously Hypertensive Rat (SHR), with nonsynonymous variants in proteins of oxidative phosphorylation demonstrated increased aerobic treadmill running capacity (p<0.05) and corresponding decreased levels of pro‐oxidant reactive oxygen species (p<0.05) compared to the inbred Dahl S rat with S rat mitochondrial genome. Thus, increased pro‐oxidant stress caused by the mtDNA of S rat, which demonstrated lower aerobic running capacity, can be restored by substitution with the mtDNA of SHR. These results provide the first direct evidence linking naturally occurring variation in the mtDNA, independent of variation in the nuclear genome, to inherited variation in aerobic fitness. These novel conplastic strains serve as invaluable tools to further dissect the relationship between aerobic fitness and cardiovascular disease progression