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.

超过1/5000的儿童出生时患有遗传性线粒体疾病，其中30-40%是复合体I (CI)导致心肌病心力衰竭和死亡的缺陷很大一部分慢性病 （糖尿病，冠状动脉疾病，心力衰竭，衰老）发展线粒体CI缺陷是关键因素 促进疾病进展和心脏并发症。将CI缺陷与以下疾病联系起来的致病机制 心脏病包括能量缺乏、氧化应激和[NADH]增加。无论是遗传的还是后天的， 线粒体CI缺陷无法治愈。我们提出了一种新的治疗靶点， 线粒体心肌病的代谢和功能。本项目的目标是确定 线粒体酶，烟酰胺核苷酸转氢酶（NNT），是维持心脏脂肪代谢所必需的。 在还原性应激条件下（增加的NADH），酸（FA）β-氧化产生ATP， 线粒体CI缺陷。我们假设CI缺陷诱导的NADH积累降低了心脏功能， 氧化代谢，从而减少FA氧化和ATP生成，并诱导氧化应激。一个 完整的NNT提供了消耗过量的NADH并形成FADH 2以维持FA的替代途径 氧化和防止氧化应激和ATP耗竭，同时保护心脏功能。第一个具体目标是 以确定NNT是否是保护线粒体CI缺陷的心脏功能和结构所必需的。的 第二个具体目标是描述NNT在维持完全FA β氧化和ATP产生中的作用 在CI缺陷的线粒体中。第三个具体目标是破译NNT的贡献，正常化氧化还原 在CI缺陷线粒体中的状态和降低的氧化应激。我们的具体目标与以下目标一致： 我们的线粒体心肌病治疗研究我们将比较心脏、心肌细胞和 来自具有正常和缺失（全身和心脏特异性）CRISPR NNT敲除的小鼠的线粒体， C57 BL 6 N背景。鱼藤酮诱导的和类人NDUFS 4缺陷的心脏特异性CI缺陷将被研究。 采用预期结果将确定NNT是否是一个潜在的治疗靶点，以保护心脏氧化 线粒体心肌病的代谢和功能。