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：
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
项目类别：
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

项目摘要

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量的主要来源，而且是高度协调的协调者。复杂的代谢系统需要沟通，因此我们的长期利益在于线粒体如何传递信息来调节代谢稳态。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编码在线粒体基因组的鉴定提供了护脑素（一种在线粒体 DNA 中编码的肽）。我们最近发现了一种线粒体通讯的范式转换调节机制。线粒体 DNA 中编码的新型肽，并将其命名为 MOTS-c（线粒体内 ORF） MOTS-c 作用于骨骼肌并促进细胞葡萄糖和脂肪酸的产生在小鼠中，MOTS-c 通过叶酸-AMPK 途径介导的代谢调节葡萄糖稳态。我们还获得了证据，可以预防高脂肪喂养的幼鼠的肥胖和胰岛素抵抗。支持代谢衰老的 MOTS-c 依赖性调节：(i) 小鼠中 MOTS-c 水平随着年龄的增长而下降循环和骨骼肌伴随肌肉胰岛素抵抗的发展，并且（ii）注射 MOTS-c 一周足以逆转全身年龄依赖性肌肉胰岛素抵抗。 MOTS-c 是叶酸-AMPK 通路的线粒体编码调节因子，可促进代谢稳态以及恢复 MOTS-c 年龄依赖性下降可以逆转代谢我们建议研究 (i) 衰老对 MOTS-c 生物学的影响，以及 (ii) MOTS-c 的影响。 c 关于衰老代谢。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。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 的作用。 MOTS-c 调节年轻与衰老原代肌肉细胞的细胞代谢的目的 3 将测试叶酸。 AMPK 通路在衰老过程中介导 MOTS-c 依赖性代谢。新颖的“以线粒体为中心”的机制层来调节衰老代谢，并提供了新的途径年龄依赖性代谢状况的治疗目标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2017-05
期刊：
影响因子：
9.8
作者：
Di Biase, Stefano;Shim, Hong Seok;Kim, Kyung Hwa;Vinciguerra, Manlio;Rappa, Francesca;Wei, Min;Brandhorst, Sebastian;Cappello, Francesco;Mirzaei, Hamed;Lee, Changhan;Longo, Valter D
通讯作者：
Longo, Valter D

Nuclear transcriptional regulation by mitochondrial-encoded MOTS-c.

线粒体编码的 MOTS-c 的核转录调节。