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: 9932647
• 负责人: Changhan Lee
• 金额: $ 7.43万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9932647
• 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; resilience; therapeutic target

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.

抽象的 线粒体不仅是细胞能的主要来源，而且还可以作为高度的协调员 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。线粒体信号传导具有 出现是衰老的关键调节器，但迄今为止描述的信号未编码 线粒体基因组。人素（在线粒体DNA中编码的肽）的鉴定提供了 线粒体交流的范式转移调节机制。我们最近发现了一个 在线粒体DNA中编码的新型肽，并将其命名为MOTS-C（线粒体ORF 十二个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调节葡萄糖稳态和 防止高脂喂养小鼠的肥胖和胰岛素抵抗。我们还获得了证据 支持代谢衰老的MOTS-C依赖性调节：（i）小鼠的MOTS-C水平随着年龄的增长而下降 循环和骨骼肌与肌肉胰岛素抵抗的发展以及（ii）的发展 全身注射MOTS-C一个星期充分反转年龄依赖性肌肉胰岛素抵抗。我们 假设MOTS-C是促进的叶酸-AMPK途径的线粒体编码调节剂 代谢稳态和恢复与MOTS-C年龄相关的下降可以逆转代谢 老化。我们建议研究（i）衰老对MOTS-C生物学的影响，相反（ii）mots-的影响 C关于老化代谢。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。目标1意志 确定MOTS-C对小鼠代谢老化的影响。 AIM 2将检查 在年轻的原代肌肉细胞中，在调节的细胞代谢中的MOTS-C。 AIM 3将测试叶酸 - 在衰老过程中介导MOTS-C依赖性代谢的AMPK途径。这些发现将完全增加 新颖的“以线粒体为中心”的机械层，以调节老化代谢，并提供新的 依赖年龄的代谢条件的治疗靶标。

项目成果

Correction: Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy.

更正：禁食可调节 EGR1 并防止葡萄糖和地塞米松依赖性化疗敏感性。

• DOI: 10.1371/journal.pbio.1002603
• 发表时间: 2017
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: DiBiase,Stefano;Shim,HongSeok;Kim,KyungHwa;Vinciguerra,Manlio;Rappa,Francesca;Wei,Min;Brandhorst,Sebastian;Cappello,Francesco;Mirzaei,Hamed;Lee,Changhan;Longo,ValterD
• 通讯作者: Longo,ValterD

Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence.

• DOI: 10.1016/j.mce.2017.01.042
• 发表时间: 2017-11-05
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Choi IY;Lee C;Longo VD
• 通讯作者: Longo VD