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Removal of damaged mitochondria by alternative autophagy

通过替代自噬去除受损的线粒体

基本信息

批准号：
10630824
负责人：
Junichi Sadoshima
金额：
$ 57.15万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630824
关键词：
Aging Autophagocytosis Autophagosome Biogenesis Cardiac Cardiac Myocytes ChIP-seq Chronic Chronic Phase Consumption Development Diabetes Mellitus Differentiation and Growth Excision Functional disorder Funding Genes Genetic Transcription Goals Heart Heart Diseases Heart Hypertrophy Heart failure High Fat Diet Homeostasis Impairment Inflammation Intervention Ischemia Knockout Mice Knowledge Mediating Metabolism Mitochondria Molecular Morphology Mus Myocardial dysfunction Organelles Parkin Pathologic Phase Play Production Property Proteins Quality Control RIPK1 gene Role Stress TFE3 gene Testing Transcription Coactivator Up-Regulation cell type diabetic cardiomyopathy diabetic patient heart cell improved in vivo lipidomics loss of function mitochondrial dysfunction mouse model myocardial injury novel obese person prevent programs protein complex response transcriptome

项目摘要

Summary Mitochondria are central intracellular organelles that mediate metabolism and ATP production. In order to maintain the function of mitochondria during stress, cardiomyocytes (CMs) have multiple layers of quality control mechanisms mediating mitochondrial fission/fusion, degradation and biogenesis. Mitophagy, a mitochondria-selective form of autophagy, is a major mechanism of degradation of damaged mitochondria and protects the heart against heart failure. In general, mitophagy is induced by the same molecular mechanisms commonly used by general autophagy, including “autophagy-related” (Atg) molecules, and additional molecules, including Pink1/Parkin. However, increasing lines of evidence suggest that mitophagy is also induced independently of conventional autophagy. During the past funding cycle, we have shown that an unconventional form of mitophagy plays a more critical role in protecting the heart during ischemia than the conventional form of mitophagy. This unconventional form of mitophagy, called alternative mitophagy, utilizes molecular machinery distinct from that used by conventional mitophagy, namely the Ulk1-Rab9-Rip1-Drp1 protein complex. Currently, the functional significance and the molecular mechanisms of alternative mitophagy remain poorly understood. Our long-term goal is to demonstrate the functional significance of alternative mitophagy in the heart during chronic and more pathologically relevant conditions in vivo, elucidate the underlying molecular mechanisms, and eventually apply our knowledge to treat heart disease by stimulating alternative mitophagy. Interestingly, although conventional autophagy and mitophagy are activated in response to high fat diet (HFD) consumption in the mouse model of diabetic cardiomyopathy, their activation is transient and they protect the heart only during the early phase of HFD consumption. On the other hand, an unconventional form of mitophagy is activated in a more prolonged manner and appears to play an essential role in protecting the heart during the chronic phase of HFD consumption. We here hypothesize that alternative mitophagy is the predominant form of mitophagy in the heart during the chronic phase of HFD consumption and plays an essential role in protecting the heart against diabetic cardiomyopathy. Alternative mitophagy is activated through a TFE3-dependent transcriptional program and the direct association of a large protein complex, containing Drp1 and Drp1 interacting proteins, with mitochondria. We will test our hypothesis using unique indicators of mitophagy, genetically altered mouse models, morphological analyses, including immunogold analyses, lipidomics, transcriptome analyses, and ChIP-sequencing analyses. Our study will demonstrate a novel and targetable mitochondrial quality control mechanism during the chronic development of diabetic cardiomyopathy. Our study should lead to the development of novel interventions to maintain the quality of mitochondria in diabetic patients and alleviate their cardiac complications, including cardiac hypertrophy/dysfunction, lipotoxicity, and inflammation.

概括线粒体是介导新陈代谢和 ATP 产生的核心细胞内细胞器。为了在应激期间维持线粒体功能，心肌细胞（CM）具有多层质量介导线粒体裂变/融合、降解和生物发生的控制机制。线粒体自噬，线粒体选择性形式的自噬，是受损线粒体降解的主要机制保护心脏免受心力衰竭。一般来说，线粒体自噬是由相同的分子机制诱导的一般自噬常用的分子，包括“自噬相关”（Atg）分子，以及其他分子，包括 Pink1/Parkin。然而，越来越多的证据表明线粒体自噬也独立于传统的自噬诱导。在过去的融资周期中，我们已经表明与线粒体自噬相比，非常规形式的线粒体自噬在保护缺血期间的心脏方面发挥着更重要的作用。线粒体自噬的常规形式。这种非常规形式的线粒体自噬，称为替代线粒体自噬，利用与传统线粒体自噬所使用的分子机制不同，即 Ulk1-Rab9-Rip1-Drp1 蛋白质复合物。目前，替代线粒体自噬的功能意义和分子机制仍然知之甚少。我们的长期目标是展示替代品的功能意义在慢性和更病理相关的体内条件下心脏中的线粒体自噬，阐明了潜在的分子机制，并最终应用我们的知识通过刺激来治疗心脏病替代线粒体自噬。有趣的是，尽管传统的自噬和线粒体自噬在响应中被激活对于糖尿病心肌病小鼠模型中的高脂肪饮食（HFD）消耗，它们的激活是短暂的它们仅在食用 HFD 的早期阶段保护心脏。另一方面，一个非常规形式的线粒体自噬以更长时间的方式被激活，并且似乎发挥着重要作用在 HFD 消耗的慢性阶段具有保护心脏的作用。我们在这里假设替代性线粒体自噬是心脏慢性期线粒体自噬的主要形式食用 HFD 在保护心脏免受糖尿病性心肌病方面发挥着重要作用。替代性线粒体自噬是通过 TFE3 依赖的转录程序激活的，并且直接包含 Drp1 和 Drp1 相互作用蛋白的大型蛋白质复合物的关联线粒体。我们将使用独特的线粒体自噬指标、基因改造小鼠来检验我们的假设模型、形态学分析，包括免疫金分析、脂质组学、转录组分析，以及 ChIP 测序分析。我们的研究将展示一种新颖且有针对性的线粒体质量控制糖尿病心肌病慢性发展过程中的机制。我们的研究应该导致开发新的干预措施以维持糖尿病患者线粒体的质量并缓解他们的心脏并发症，包括心脏肥大/功能障碍、脂毒性和炎症。