Lapointe Jérôme, Hekimi Siegfried
Department of Biology, McGill University, Montreal H3A 1B1, Canada.
J Biol Chem. 2008 Sep 19;283(38):26217-27. doi: 10.1074/jbc.M803287200. Epub 2008 Jul 17.
Reduced activity of CLK-1/MCLK1 (also known as COQ7), a mitochondrial enzyme that is necessary for ubiquinone biosynthesis, prolongs the lifespan of nematodes and mice by a mechanism that is distinct from that of the insulin signaling pathway. Here we show that 2-fold reduction of MCLK1 expression in mice reveals an additional function for the protein, as this level of reduction does not affect ubiquinone levels yet affects mitochondrial function substantially. Indeed, we observe that the phenotype of young Mclk1(+/-) mutants includes a severe reduction of mitochondrial electron transport, ATP synthesis, and total nicotinamide adenine dinucleotide (NAD(tot)) pool size as well as an alteration in the activity of key enzymes of the tricarboxylic acid cycle. Surprisingly, we also find that Mclk1 heterozygosity leads to a dramatic increase in mitochondrial oxidative stress by a variety of measures. Furthermore, we find that the mitochondrial dysfunction is accompanied by a decrease in oxidative damage to cytosolic proteins as well as by a decrease in plasma isoprostanes, a systemic biomarker of oxidative stress and aging. We propose a mechanism for the conjunction of low ATP levels, high mitochondrial oxidative stress, and low non-mitochondrial oxidative damage in a long-lived mutant. Our model helps to clarify the relationship between energy metabolism and the aging process and suggests the need for a reformulation of the mitochondrial oxidative stress theory of aging.
CLK-1/MCLK1（也称为COQ7）是一种线粒体酶，对泛醌生物合成至关重要，其活性降低可通过一种不同于胰岛素信号通路的机制延长线虫和小鼠的寿命。在此，我们表明，小鼠中MCLK1表达降低两倍揭示了该蛋白的另一种功能，因为这种降低水平并不影响泛醌水平，但却显著影响线粒体功能。实际上，我们观察到年轻的Mclk1(+/-)突变体的表型包括线粒体电子传递、ATP合成以及总烟酰胺腺嘌呤二核苷酸（NAD(tot)）池大小严重降低，以及三羧酸循环关键酶活性改变。令人惊讶的是，我们还发现通过多种测量方法，Mclk1杂合性会导致线粒体氧化应激显著增加。此外，我们发现线粒体功能障碍伴随着胞质蛋白氧化损伤的减少以及血浆异前列腺素的减少，血浆异前列腺素是氧化应激和衰老的一种全身生物标志物。我们提出了一种机制，用于解释长寿突变体中低ATP水平、高线粒体氧化应激和低非线粒体氧化损伤之间的关联。我们的模型有助于阐明能量代谢与衰老过程之间的关系，并表明需要重新阐述线粒体氧化应激衰老理论。
