Novel Regulators of Aging Metabolism Encoded in the Mitochondrial Genome

 描述(申请人提供)：线粒体不仅是细胞能量的主要来源，也是高度复杂的新陈代谢系统的协调者。协调需要交流，因此我们的长期兴趣在于线粒体如何传递信息来调节新陈代谢平衡。线粒体信号已成为衰老的关键调节因素，但迄今已被描述的信号并未在线粒体基因组中编码。人蛋白是一种编码在线粒体DNA中的多肽，它的发现为线粒体通讯提供了一种范式转换的调节机制。我们最近发现了一种新的编码在线粒体DNA中的多肽，并将其命名为MOTS-c(12个S rRNA中的线粒体ORF)。MOTS-c通过叶酸-AMPK途径作用于骨骼肌，促进细胞葡萄糖和脂肪酸代谢。在小鼠中，mots-c调节葡萄糖的动态平衡，并防止高脂喂养的幼鼠肥胖和胰岛素抵抗。我们还获得了支持MOTS-c依赖的代谢衰老调节的证据：(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，以及(Ii)全身注射MOTS-c一周足以逆转年龄依赖性肌肉的胰岛素抵抗。我们假设MOTS-c是促进代谢动态平衡的叶酸-AMPK途径的线粒体编码的调节器，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对衰老代谢的影响。我们将采取自上而下的方法，有3个目标来检验我们的假设。目的1确定MOTS-c对小鼠代谢衰老的年龄依赖性影响。目的2研究MOTS-c在年轻和老年原代肌肉细胞中调节细胞代谢的作用。目的3将测试叶酸-AMPK通路在介导MOTS-c依赖的衰老代谢中的作用。这些发现将为衰老代谢的调节增加一个全新的以线粒体为中心的机械层，并为年龄依赖性代谢疾病提供一个新的治疗靶点。

 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.