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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：
10305935
负责人：
Junichi Sadoshima
金额：
$ 57.15万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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/10305935
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 Lead Mediating Metabolism Mitochondria Molecular Morphology Mus Myocardial dysfunction Organelles 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 parkin gene/protein 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.

总结