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

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：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进行调节。线粒体信号传导已成为衰老的关键调节因子，但迄今为止所描述的信号并未在线粒体基因组中编码。护脑素是一种在线粒体中编码的肽。 DNA 提供了线粒体通讯的范式转换调节机制，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（MOTS-c 中的线粒体 ORF）作用于骨骼肌和。通过叶酸-AMPK 途径促进细胞葡萄糖和脂肪酸代谢在小鼠中，MOTS-c 调节葡萄糖稳态并预防高脂肪人群的肥胖和胰岛素抵抗。我们还获得了支持 MOTS-c 依赖性调节代谢衰老的证据：(i) 小鼠中 MOTS-c 水平随着循环和骨骼肌年龄的增长而下降，同时伴随着肌肉胰岛素抵抗的发展。全身注射 MOTS-c 一周，足以逆转年龄依赖性肌肉胰岛素抵抗，我们发现 MOTS-c 是叶酸-AMPK 途径的线粒体编码调节剂，可促进代谢稳态。恢复 MOTS-c 的年龄依赖性衰退可以逆转代谢衰老。我们将研究 (i) 衰老对 MOTS-c 生物学的影响，以及相反的 (ii) MOTS-c 对衰老代谢的影响。自上而下的方法 3 旨在检验我们的假设。目标 1 将确定 MOTS-c 对小鼠代谢衰老的年龄依赖性影响，目标 2 将检查 MOTS-c 在调节年轻与老年原代细胞代谢中的作用。肌肉细胞。目标 3 将测试叶酸 AMPK 通路在衰老过程中介导 MOTS-c 依赖性代谢的作用。这些发现将为衰老代谢的调节添加全新的“以线粒体为中心”的机制层，并为年龄相关的疾病提供新的治疗靶点。依赖的代谢条件。