title: Compensatory elevation of voluntary activity in mouse mutants with impaired mitochondrial energy metabolism.
abstract: 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 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.
authors.affiliation: Department of Biology, McGill University, Montréal, Quebec, Canada Agriculture and Agri-Food Canada, 2000 College St., Sherbrooke, J1M 0C8, Quebec, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lapointe
authors.affiliation: Department of Biology, McGill University, Montréal, Quebec, Canada Department of Pharmacology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada.
authors.forename: Bryan
authors.initials: BG
authors.lastname: Hughes
authors.affiliation: Department of Biology, McGill University, Montréal, Quebec, Canada.
authors.forename: Eve
authors.initials: E
authors.lastname: Bigras
authors.affiliation: Department of Biology, McGill University, Montréal, Quebec, Canada.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hekimi
keywords: Behavior; Mclk1 RISP Sod2; energy metabolism and oxidative stress; mitochondria