Novel Regulators of Aging Metabolism Encoded in the Mitochondrial Genome

摘要 线粒体不仅是细胞能量的主要来源，而且也是细胞内高能量代谢的协调者。 复杂的代谢系统协调需要沟通，因此我们的长期利益是 线粒体如何传递信息以调节代谢稳态。线粒体信号传递 作为衰老的关键调节器出现，但迄今为止所描述的信号并没有编码在大脑中。 线粒体基因组Humanin是一种在线粒体DNA中编码的肽， 线粒体通讯的范式转换调节机制。我们最近发现了一个 在线粒体DNA中编码一种新的肽，并将其命名为MOTS-c（线粒体内的ORF）。 12个S rRNA）。MOTS-c作用于骨骼肌并促进细胞葡萄糖和脂肪酸 代谢，由叶酸-AMPK途径介导。在小鼠中，MOTS-c调节葡萄糖稳态， 预防高脂肪喂养的幼鼠肥胖和胰岛素抵抗。我们还获得了证据 支持代谢老化的MOTS-c依赖性调节：（i）小鼠中的MOTS-c水平随着年龄的增长而下降， 循环和骨骼肌伴随着肌肉胰岛素抵抗的发展，和（ii） 全身注射MOTS-c一周足以逆转年龄依赖性肌肉胰岛素抵抗。我们 假设MOTS-c是叶酸-AMPK途径的唾液酸编码的调节物，其促进 代谢稳态和恢复MOTS-c的年龄依赖性下降可以逆转代谢 衰老我们建议研究（i）衰老对MOTS-c生物学的影响，反之（ii）MOTS-c的影响。 c关于衰老代谢。我们将采取自上而下的方法，以3个目标来测试我们的假设。目标1将 确定MOTS-c对小鼠代谢老化的年龄依赖性影响。目标2将审查 MOTS-c在年轻与老年原代肌细胞中调节细胞代谢。目标3将测试叶酸- AMPK通路介导衰老过程中MOTS-c依赖性代谢。这些发现将增加一个完全 新的“以骨骼为中心”的机制层来调节衰老代谢，并提供新的 年龄依赖性代谢疾病的治疗靶点。

ABSTRACT Mitochondria not only serve as the major source of cellular energy, but also as a coordinator of the highly sophisticated metabolic system. Coordination requires communication, and thus our long-term interest is in how mitochondria transmit messages to regulate metabolic homeostasis. Mitochondrial signaling has emerged as a key regulator of aging, but signals that have been described to date are not encoded in the mitochondrial genome. The identification of Humanin, a peptide encoded in the mitochondrial DNA, provided a paradigm-shifting regulatory mechanism of mitochondrial communication. We have recently discovered a novel peptide encoded within the mitochondrial DNA and named it MOTS-c (Mitochondrial ORF within the Twelve S rRNA). MOTS-c acts on the skeletal muscle and promotes cellular glucose and fatty acid metabolism, mediated by the folate-AMPK pathway. In mice, MOTS-c regulates glucose homeostasis and prevents obesity and insulin-resistance in high-fat fed young mice. We have also obtained evidence supporting MOTS-c-dependent regulation of metabolic aging: (i) MOTS-c levels in mice decline with age in circulation and skeletal muscle concomitantly with the development of muscle insulin-resistance and (ii) systemic injection of MOTS-c for a week sufficiently reversed age-dependent muscle insulin resistance. We hypothesize that MOTS-c is a mitochondrial-encoded regulator of the folate-AMPK pathway that promotes metabolic homeostasis and that restoring the age-dependent decline of MOTS-c can reverse metabolic aging. We propose to study (i) the impact of aging on MOTS-c biology and conversely (ii) the effect of MOTS- c on aging metabolism. We will take a top-down approach with 3 aims to test our hypothesis. Aim 1 will determine the age-dependent impact of MOTS-c on metabolic aging in mice. Aim 2 will examine the role of MOTS-c in regulating cellular metabolism in young vs aged primary muscle cells. Aim 3 will test the folate- AMPK pathway in mediating MOTS-c-dependent metabolism during aging. These findings will add an entirely novel ‘mitochondrial-centric’ mechanistic layer to the regulation of aging metabolism, and provide a new therapeutic target for age-dependent metabolic conditions.