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Interplay between mitophagy and substrate utilization in heart failure progression

线粒体自噬和底物利用在心力衰竭进展中的相互作用

基本信息

批准号：
10534749
负责人：
Nuo Sun
金额：
$ 52.33万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-06 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534749
关键词：
Adult Affect Attenuated Bioenergetics Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Physiology Cardiovascular system Carnitine Palmitoyltransferase I Deubiquitinating Enzyme Deubiquitination Development Energy Metabolism Exhibits Fatty Acids Genes Genetic Glucose Goals Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Human Impairment In Vitro Inner mitochondrial membrane Intervention Kinetics Knock-out Knowledge Link Lysosomes Mediating Metabolic Metabolism Mitochondria Mitochondrial Membrane Protein Modeling Molecular Mus Myocardial Nuclear Outer Mitochondrial Membrane PINK1 gene PTEN gene Parkin Pathologic Pathway interactions Peptide Hydrolases Phenotype Phosphotransferases Physiological Play Production Proteins Quality Control Reaction Reagent Regulation Research Research Proposals Role Signal Pathway Stress Testing Therapeutic Tissues Ubiquitin Ubiquitination cardioprotection carnitine palmitoyltransferase 2 deficiency functional decline gain of function genetic analysis heart function improved in vivo in vivo monitoring induced pluripotent stem cell inhibitor innovation insight long chain fatty acid mitochondrial dysfunction mitochondrial metabolism mouse model novel novel therapeutic intervention oxidation pharmacologic premature presenilin preservation pressure programs receptor response rhomboid spatiotemporal therapeutic target treatment strategy ubiquitin isopeptidase ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Mitochondrial dysfunction and altered mitochondrial metabolism have been implicated in the development of heart failure (HF). Mitophagy is a specialized autophagic pathway that mediates the lysosome-dependent clearance of damaged mitochondria, and is essential for mitochondrial quality control. However, our current knowledge regarding mitophagy in the heart and how it relates to myocardial metabolism is limited. Under normal conditions, the heart relies predominantly on fatty acid β-oxidation (FAO) to fuel ATP production. In contrast, a failing or hypertrophied heart usually shows impaired FAO and increased reliance on glucose utilization. Despite significant advancements in understanding the regulatory programs that attenuate FAO, it is unclear how shifts in myocardial substrate utilization contribute to the regulation of mitophagy. Therefore, this research proposal focuses on the functional significance of cardiac mitophagy in response to altered myocardial substrate utilization that occurs, for instance, in the setting of impaired FAO. The goal of this project is to delineate the novel mechanistic link between mitophagy and myocardial substrate utilization in the heart, as well as to determine whether mitophagy represents a novel mechanism and therapeutic target for the treatment of heart disease. These studies will be facilitated by our recently described mt-Keima mouse model to monitor in vivo cardiac mitophagy, as well as a set of innovative reagents to genetically and pharmacologically modulate mitophagic flux. To directly assess the role of FAO in the heart, we have generated mice with cardiomyocyte-specific deletion of CPT2 (CPT2-cKO), encoding a single gene required for FAO. We have demonstrated a decline in mitophagy precedes the development of impaired cardiac function in FAO-deficient hearts. Our genetic analyses suggest cardiac CPT2 deletion impairs the PTEN-induced putative kinase 1 (PINK1) signaling pathway, which positively regulates mitophagy through mitochondrial ubiquitination. Augmentation of mitophagy by modulating USP30, which mediates the reverse reaction, deubiquitination on mitochondria, mitigates the functional decline in FAO deficient hearts. Therefore, in Aim 1 of the proposed studies, our goal is to define the magnitude and Kinetics of cardiac mitophagy in response to impaired FAO, as well as to dissect the underlying molecular mechanisms connecting mitophagy to myocardial substrate utilization. In Aim 2 of the proposed studies, we will genetically and pharmacologically manipulate USP30 enzymatic function in the heart using mouse models that lack USP30 or are treated with a novel USP30 inhibitor. We will determine whether the detrimental cardiac phenotype, induced by cardiac CPT2 deletion or pressure overload, could be reversed, at least partially, by restoring mitophagy in cardiomyocytes via the inhibition of USP30. Completion of the proposed studies will produce critical insights into the role of mitophagy in normal cardiovascular physiology and in pathological conditions, and will fundamentally advance our understanding of the interaction between mitochondrial metabolism and mitochondrial quality control in the heart.

项目总结