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.

概括线粒体是介导代谢和ATP产生的中央细胞内细胞器。为了在压力期间保持线粒体的功能，心肌细胞（CMS）具有多层质量控制线粒体裂变/融合，降解和生物发生的控制机制。线粒体，a 线粒体选择性的自噬形式是降解线粒体和线粒体降解的主要机制保护心脏免受心力衰竭。通常，线粒体由相同的分子机制诱导普通自噬通常使用，包括“自噬相关”（ATG）分子和其他分子，包括Pink1/Parkin。但是，越来越多的证据表明线粒体也是独立于常规自噬诱导。在过去的资金周期中，我们已经表明线粒体的非常规形式在缺血期间保护心脏中起着更关键的作用线粒体的常规形式。线粒体的这种非常规形式，称为替代线粒体，利用分子机械与常规线粒体所用的机械，即ULK1-RAB9-RIP1-DRP1 蛋白质复合物。目前，替代线粒体的功能意义和分子机制保持不当理解。我们的长期目标是证明替代方案的功能意义在体内慢性且在病理上相关的情况下，心脏中的线粒体在体内阐明潜在的分子机制，有时将我们的知识通过刺激来治疗心脏病替代线粒体。有趣的是，尽管传统的自噬和线粒体被激活以响应在糖尿病心肌病小鼠模型中，高脂肪饮食（HFD）消耗，它们的激活是短暂的它们只有在HFD消费的早期才能保护心脏。另一方面，线粒体的非常规形式以更延长的方式激活，并且似乎起着必不可少的在HFD消费的慢性阶段保护心脏方面的作用。我们在这里假设替代线粒体是在心脏中主要形式的线粒体形式 HFD消耗并在保护心脏侵害糖尿病心肌病中起着至关重要的作用。通过TFE3依赖性转录程序和直接激活替代线粒体大型蛋白质复合物的缔合，其中包含DRP1和DRP1相互作用蛋白与线粒体。我们将使用线粒体，遗传改变的小鼠的独特指标检验我们的假设模型，形态学分析，包括免疫元分析，脂质组学，转录组分析和芯片序列分析。我们的研究将证明一种新颖且具有目标的线粒体质量控制糖尿病心肌病长期发育过程中的机制。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减轻它们的心脏并发症，包括心脏肥大/功能障碍，脂肪毒性和炎症。