Novel Regulators of Aging Metabolism Encoded in the Mitochondrial Genome

线粒体基因组编码的衰老代谢的新型调节因子

• 批准号: 9923533
• 负责人: Changhan Lee
• 金额: $ 33.83万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923533
• 关键词: Age; Aging; Animals; Biological Markers; Biology; Blood Circulation; Carbon; Cells; Collaborations; Communication; Complex; Coupling; Diabetes Mellitus; Diet; Enzymes; Fatty acid glycerol esters; Folic Acid; Foundations; Genetic; Gerontology; Glucose; Goals; High Fat Diet; Homeostasis; Influentials; Injections; Insulin Resistance; Knockout Mice; Light; Link; Lipids; Longevity; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Metformin; Mitochondria; Mitochondrial DNA; Molecular; Mus; Muscle; Muscle Cells; Muscle Development; Names; Nuclear; Obesity; Open Reading Frames; Organelles; Pathway interactions; Peptides; Pharmaceutical Preparations; Physical Performance; Proteins; Proteomics; Purines; Reactive Oxygen Species; Regulation; Respiration; Ribosomal RNA; Role; Schools; Signal Transduction; Skeletal Muscle; Source; System; Testing; Tissues; Work; age effect; age group; age related; aged; base; blood glucose regulation; circulating biomarkers; cytochrome c; fatty acid metabolism; gain of function; humanin; insulin sensitivity; interest; knock-down; metabolic phenotype; metabolomics; mitochondrial genome; mouse model; new therapeutic target; novel; overexpression; prevent; public health relevance; resilience; therapeutic target

 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.

 描述（由应用程序提供）：线粒体不仅是细胞能量的主要来源，而且是高度复杂的代谢系统的协调员。协调需要沟通，因此我们的长期利益在于线粒体如何传输信息以调节代谢稳态。线粒体信号已成为衰老的关键调节剂，但迄今为止所描述的信号未在线粒体基因组中编码。人类的鉴定，即线粒体DNA中编码的肽，提供了线粒体通信的范式转移调节机制。我们最近发现了一种在线粒体DNA中编码的新型肽，并将其命名为Mots-C（十二个S rRNA中的线粒体ORF）。 MOTS-C作用于骨骼肌，并促进由叶酸AMPK途径介导的细胞葡萄糖和脂肪酸代谢。在小鼠中，MOTS-C调节葡萄糖稳态，并防止高脂喂养小鼠的肥胖和胰岛素抵抗。我们还获得了支持MOTS-C依赖性衰老调节的证据：（i）小鼠中的MOTS-C水平随着年龄的年龄而下降，随着循环年龄的增长和骨骼肌的下降，随着肌肉胰岛素抵抗的发展，以及（ii）一周的MOTS-C系统性注入一周，足以反抗年龄依赖年龄依赖性的肌肉胰岛素抵抗。我们假设MOTS-C是叶酸AMPK途径的线粒体编码调节剂，可促进代谢稳态，并且恢复MOTS-C的年龄依赖性下降可以反向代谢衰老。我们建议研究（i）衰老对MOTS-C生物学的影响，相反（ii）MOTS-C对衰老代谢的影响。我们将采用一种自上而下的方法，其目的是检验我们的假设。 AIM 1将确定MOTS-C对小鼠代谢老化的影响。 AIM 2将检查MOTS-C在控制年轻的原代肌肉细胞中控制细胞代谢中的作用。 AIM 3将测试叶酸AMPK途径在介导MOTS-C依赖性代谢过程中的叶酸AMPK途径。这些发现将为衰老代谢的调节增加一个全新的“线粒体中心”机械层，并为年龄依赖性代谢条件提供了新的治疗靶标。