Nicotinamide nucleotide transhydrogenase and bioenergetic metabolism in complex I defective cardiac mitochondria

烟酰胺核苷酸转氢酶和复合物 I 缺陷心脏线粒体中的生物能代谢

• 批准号: 10360118
• 负责人: Georgeta Mariana Rosca
• 金额: $ 43.95万
• 依托单位: CENTRAL MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360118
• 关键词: ATP Synthesis Pathway; Adrenal gland hypofunction; Affect; Aging; Animals; Antioxidants; Arrhythmia; Back; Bioenergetics; Bypass; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Respiration; Cessation of life; Child; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Consumption; Coronary Arteriosclerosis; Data; Defect; Diabetes Mellitus; Disease; Disease Progression; Electron Transport; Electron Transport Complex III; Enzymes; FADH2; Fatty Acids; Generations; Goals; Heart; Heart Diseases; Heart failure; Human; Individual; Inherited; Inner mitochondrial membrane; Knock-out; Lead; Link; Lung; Maintenance; Membrane; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Mus; Mutation; Myocardial dysfunction; NAD(P)+ transhydrogenase; NADP; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxides; Pathogenicity; Pathway interactions; Peroxides; Pharmacology; Process; Production; Prognosis; Proton-Motive Force; Protons; Reporting; Research; Retinal Photoreceptors; Role; Rotenone; Route; Structure; fatty acid oxidation; feeding; heart function; heart preservation; human subject; mouse model; negative affect; new therapeutic target; oxidation; prevent; stress reduction; therapeutic target; translational impact

More than 1 in 5000 children are born with inherited mitochondrial diseases from which 30-40% are complex I (CI) defects that lead to cardiomyopathy, heart failure and death. A large proportion of chronic conditions (diabetes, coronary artery disease, heart failure, aging) develop mitochondrial CI defects that are key factors promoting disease progression and cardiac complications. Pathogenic mechanisms that link CI defect with heart disease include energy deficit, oxidative stress, and an increased [NADH]. Either inherited or acquired, mitochondrial CI defects have no cure. We propose a novel therapeutic target that preserves cardiac oxidative metabolism and function in mitochondrial cardiomyopathies. The objective of this project is to determine if the mitochondrial enzyme, nicotinamide nucleotide transhydrogenase (NNT), is necessary to sustain cardiac fatty acid (FA) β-oxidation for ATP production under conditions of reductive stress (increased NADH) caused by a mitochondrial CI defect. We hypothesize that NADH accumulation induced by a CI defect decreases cardiac oxidative metabolism thus decreasing FA oxidation and ATP generation, and inducing oxidative stress. An intact NNT provides an alternate route to consume the excessive NADH and form FADH2 to maintain FA oxidation and prevent oxidative stress and ATP depletion while preserving cardiac function. First specific aim is to determine if NNT is necessary to protect the heart function and structure in mitochondrial CI defect. The second specific aim is to delineate the role of NNT in sustaining complete FA β-oxidation and ATP production in CI defective mitochondria. The third specific aim is to decipher the contribution of NNT to normalize redox status and decrease oxidative stress in CI defective mitochondria. Our specific objective aligns with the goal of our research to cure mitochondrial cardiomyopathies. We will compare hearts, cardiomyocytes and mitochondria from mice with normal and absent (systemic and cardiac specific) CRISPR NNT knockout on the C57BL6N background. Rotenone-induced and human-like NDUFS4-deficient cardiac specific CI defects will be used. Expected outcomes will determine if NNT is a potential therapeutic target to preserve cardiac oxidative metabolism and function in mitochondrial cardiomyopathy.

每5000名儿童中就有1名出生时患有遗传性线粒体疾病，其中30%-40%是复合体 (Ci)导致心肌病、心力衰竭和死亡的缺陷。相当大比例的慢性病 (糖尿病、冠状动脉疾病、心力衰竭、衰老)发生线粒体CI缺陷，这是关键因素 促进疾病进展和心脏并发症。CI缺陷与致病机制的关系 心脏病包括能量缺乏、氧化应激和[NADH]升高。无论是继承的还是后天获得的， 线粒体CI缺陷无法治愈。我们提出了一种新的治疗靶点，以保护心脏氧化 线粒体心肌病的代谢和功能。该项目的目标是确定 线粒体酶，烟酰胺核苷酸转氢酶(NNT)是维持心脏脂肪所必需的。 酸性(FA)β氧化作用在还原胁迫(增加NADH)条件下的作用 线粒体CI缺陷症。我们假设脑梗塞缺陷引起的NADH积聚会降低心脏 氧化代谢从而减少FA的氧化和ATP的生成，并诱导氧化应激。一个 完整的NNT提供了一种替代途径来消耗过量的NADH并形成FADH2来维持FA 氧化，防止氧化应激和ATP消耗，同时保护心脏功能。第一个具体目标是 目的：探讨NNT是否对线粒体CI缺陷症的心脏功能和结构具有保护作用。这个 第二个特定的目的是描述NNT在维持完整的FAβ氧化和ATP产生中的作用 脑梗塞患者的线粒体有缺陷。第三个具体目标是破译NNT对氧化还原正常化的贡献 脑梗塞缺陷线粒体的氧化应激状态和降低。我们的具体目标与 我们治疗线粒体心肌病的研究。我们将比较心脏、心肌细胞和 正常和缺失(系统和心脏特异性)CRISPR NNT基因敲除小鼠的线粒体 C57BL6N背景。鱼藤酮诱导和类人NDUFS4缺陷的心脏特异性CI缺陷将是 使用。预期结果将决定NNT是否是保护心脏氧化的潜在治疗靶点 线粒体心肌病的代谢和功能。