Novel Regulators of Aging Metabolism Encoded in the Mitochondrial Genome

 描述（由申请人提供）：线粒体不仅是细胞能量的主要来源，也是高度复杂的代谢系统的协调者。协调需要沟通，因此我们的长期兴趣是线粒体如何传递信息以调节代谢稳态。线粒体信号已经成为衰老的关键调节因子，但迄今为止已经描述的信号不在线粒体基因组中编码。Humanin是一种存在于线粒体DNA中的多肽，它的发现为线粒体通讯的调控机制提供了新的范式。我们最近发现了一种新的编码在线粒体DNA中的肽，并将其命名为MOTS-c（Mitochondrial ORF within the Twelve 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调节葡萄糖稳态并防止高脂肪喂养的年轻小鼠的肥胖和胰岛素抵抗。我们还获得了支持代谢老化的MOTS-c依赖性调节的证据：（i）小鼠循环和骨骼肌中的MOTS-c水平随着年龄的增长而下降，同时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通路的一种神经编码调节因子，促进代谢稳态，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，以及相反地（ii）MOTS-c对衰老代谢的影响。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。目的1将确定MOTS-c对小鼠代谢衰老的年龄依赖性影响。目的2将研究MOTS-c在年轻与老年初级肌细胞中调节细胞代谢的作用。目的3将测试叶酸- AMPK途径在衰老过程中介导MOTS-c依赖性代谢。这些发现将为衰老代谢的调节增加一个全新的“以骨骼为中心”的机制层，并为年龄依赖性代谢疾病提供新的治疗靶点。

 DESCRIPTION (provided by applicant): 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.