Lapointe Jérôme, Hughes Bryan, Bigras Eve, Hekimi Siegfried
Department of Biology, McGill University, Montréal, Quebec, Canada Agriculture and Agri-Food Canada, 2000 College St., Sherbrooke, J1M 0C8, Quebec, Canada.
Department of Biology, McGill University, Montréal, Quebec, Canada Department of Pharmacology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada.
Physiol Rep. 2014 Nov 20;2(11). doi: 10.14814/phy2.12214. Print 2014 Nov 1.
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.
线粒体在决定全身代谢和运动能力方面起着关键作用。轻度线粒体功能障碍的基因小鼠模型为了解线粒体功能如何影响这些参数提供了契机。MCLK1（又名Coq7）是一种参与泛醌（UQ；辅酶Q）生物合成的酶。Mclk1(+/-)杂合突变体中MCLK1水平较低会导致UQ的亚线粒体分布异常、线粒体功能受损、线粒体氧化应激升高以及寿命延长。在此，我们报告，通过间接量热法测量，年轻的Mclk1(+/-)雄性小鼠而非雌性小鼠的全身代谢率显著降低。对于携带线粒体复合物III“里斯克”蛋白（RISP(+/P224S)）编码基因突变的杂合小鼠，也报道了线粒体功能障碍对能量代谢的这种性别特异性影响。我们发现，与野生型相比，Mclk1(+/-)和RISP(+/P224S)雄性小鼠都能够通过显著增加对跑步轮的自主使用来恢复其有缺陷的代谢率。然而，这种自主活动的增加并不反映它们的运动能力，我们发现，通过疲劳前跑步机跑步距离较短可以看出它们的运动能力受损。与在Mclk1(+/-)和RISP(+/P224S)突变体中观察到的情况相反，氧化应激升高和主要线粒体功能障碍的Sod2(+/-)小鼠并没有增加自主活动。我们的研究揭示了线粒体功能受损对全身能量代谢和运动行为影响的性别特异性效应，并有助于理解线粒体疾病的代谢和行为后果。
