Compensatory elevation of voluntary activity in mouse mutants with impaired mitochondrial energy metabolism

Mitochondria play a crucial role in determining whole‐body metabolism and exercise capacity. Genetic mouse models of mild mitochondrial dysfunction provide an opportunity to understand how mitochondrial function affects these parameters. MCLK 1 (a.k.a. Coq7) is an enzyme implicated in the biosynthesis of ubiquinone ( UQ ; Coenzyme Q). Low levels of MCLK 1 in Mclk1 +/− heterozygous mutants lead to abnormal sub‐mitochondrial distribution of UQ , impaired mitochondrial function, elevated mitochondrial oxidative stress, and increased lifespan. Here, we report that young Mclk1 +/− males, but not females, show a significant decrease in whole‐body metabolic rate as measured by indirect calorimetry. Such a sex‐specific effect of mitochondrial dysfunction on energy metabolism has also been reported for heterozygous mice carrying a mutation for the gene encoding the “Rieske” protein of mitochondrial complex III ( RISP +/ P224S ). We find that both Mclk1 +/− and RISP +/ P224S males are capable of restoring their defective metabolic rates by making significantly more voluntary use of a running wheel compared to wild type. However, this increase in voluntary activity does not reflect their exercise capacity, which we found to be impaired as revealed by a shorter treadmill distance run before exhaustion. In contrast to what is observed in Mclk1 +/− and RISP +/ P224S mutants, Sod2 +/− mice with elevated oxidative stress and major mitochondrial dysfunction did not increase voluntary activity. Our study reveals a sex‐specific effect on how impaired mitochondrial function impacts whole‐body energy metabolism and locomotory behavior, and contributes to the understanding of the metabolic and behavioral consequences of mitochondrial disorders.