Role of the mitochondrial LonP1 in myocardial ischemia and reperfusion injury protection

线粒体LonP1在心肌缺血再灌注损伤保护中的作用

• 批准号: 10640920
• 负责人: Venkatesh Sundararajan
• 金额: $ 38万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640920
• 关键词: Acetylation; Acute; Animals; Antioxidants; Bioenergetics; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cell Death; Cell Death Induction; Cellular biology; Cessation of life; Chronic; Clinical; Complex; Data; Dose; Down-Regulation; Electron Transport; Event; Failure; Fibrosis; Free Radicals; Gel; Generations; Glycyrrhetinic Acid; Goals; Heart; Heart Injuries; Heart failure; Heterozygote; Histologic; Homeostasis; Hypoxia; In Vitro; Infarction; Inflammatory Infiltrate; Intervention; Ischemia; Ischemic Preconditioning; Knock-out; Knockout Mice; Mediating; Mediator; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Biology; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Outcome; Oxidative Stress; Oxidative Stress Induction; Patients; Peptide Hydrolases; Physiological; Production; Proteomics; Publishing; Quality Control; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Signal Transduction; Site; Superoxides; Techniques; Terpenes; Testing; Therapeutic; Tissues; Transgenic Organisms; United States; Work; biological adaptation to stress; cardioprotection; effective therapy; heart function; high throughput screening; improved; in vivo; inhibitor; ischemic injury; mouse model; mutant; myocardial injury; novel; novel therapeutics; overexpression; oxidative damage; prevent; proteostasis; small molecule; therapeutic evaluation; tool

PROJECT SUMMARY Ischemia-reperfusion (IR) injury is a significant challenge in treating myocardial infarction (MI), the leading cause of death in the United States. Mitochondrial reactive oxygen species (mtROS) generated by electron transport chain (ETC) Complex-I are the principal mediators of IR injury. Excess mtROS generated during early IR triggers vicious cycles of free radical production promoting cardiomyocyte death. Therefore, understanding the early molecular events of reperfusion will provide new targets for developing novel interventions for limiting cardiac injury. Our published findings show that LonP1- a major mitochondrial stress response protease mitigates oxidative stress-induced damage during early IR; therefore, LonP1 could be a promising target for attenuating reperfusion injury. Our long-term goal is to leverage the mitochondrial protein quality control mechanisms of LonP1 as a pivotal point to develop therapeutic strategies for mitigating IR injury and post MI- heart failure. Our published findings show that increased LonP1 expression in the heart induced by ischemic preconditioning (IPC) or transgenic overexpression (LonTg) reduced IR injury and favors cardioprotection. Whereas, LonP1 downregulation (LONP1+/-) abrogated IPC-mediated cardioprotection. Importantly, LonTg hearts showed reduced levels of Complex-I subunits (but not Complex II-V subunit) and oxidative damage during early IR (within 30 min reperfusion) compared to NTg controls. Conversely, our additional findings show that LonP1 downregulation in cardiomyocytes upregulated Complex-I activity, increased superoxide levels, and showed early reperfusion-induced cell death activation. In addition, we have identified a small molecule activator of LonP1 that significantly reduced hypoxia-reoxygenation (H/R) induced myocyte death in a dose-dependent manner in vitro. With additional data on IR-induced acetylation of Complex-I matrix subunits and LonP1 dependent Complex-I remodeling during IR, we hypothesize that LonP1 mitigates myocardial injury by suppressing excess mtROS generation through tight regulation of Complex-I during early IR. We will test our hypothesis by the following specific aims: Aim 1 will delineate the mechanism(s) by which LonP1 modulates Complex-I levels, activity and reduces oxidative stress during IR. Aim 2 will test that LonP1 remodels Complex-I and its associated supercomplexes by degrading IR-induced post-translationally modified (PTM) Complex-I matrix subunits, thereby reduce mtROS during early IR. Aim 3 will determine the therapeutic potential of LonP1 activators in treating myocardial IR injury in vivo. By determining the molecular mechanisms of LonP1-mediated cardioprotection and the therapeutic potential of LonP1 activators, we will define the role of LonP1 in cardioprotection and develop novel therapeutic tools and strategies to mitigate IR injury.

项目总结