Compensatory elevation of voluntary activity in mouse mutants with impairedmitochondrial energy metabolism

摘要

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. MCLK1 (a.k.a. Coq7) is an enzyme implicated in the biosynthesis of ubiquinone (UQ; Coenzyme Q). Low levels of MCLK1 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 theirexercise capacity, which we found to be impaired as revealed by a shorter treadmill distance runbefore exhaustion. In contrast to what is observed inMclk1^+/− andRISP^+/P224S mutants,Sod2^+/− mice with elevated oxidative stress andmajor mitochondrial dysfunction did not increase voluntary activity. Our study reveals asex‐specific effect on how impaired mitochondrial function impacts whole‐body energymetabolism and locomotory behavior, and contributes to the understanding of the metabolic andbehavioral consequences of mitochondrial disorders.