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.

超过五千名儿童中就有一名患有遗传性线粒体疾病，其中 30-40% 为复合型 I (CI) 导致心肌病、心力衰竭和死亡的缺陷。很大一部分是慢性病 （糖尿病、冠状动脉疾病、心力衰竭、衰老）产生线粒体 CI 缺陷是关键因素 促进疾病进展和心脏并发症。 CI 缺陷与相关的致病机制 心脏病包括能量不足、氧化应激和 [NADH] 增加。无论是遗传的还是后天获得的， 线粒体 CI 缺陷无法治愈。我们提出了一种新的治疗靶点，可以保护心脏氧化 线粒体心肌病的代谢和功能。该项目的目标是确定是否 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 在由 a 引起的还原应激（NADH 增加）条件下，通过酸 (FA) β-氧化生成 ATP 线粒体 CI 缺陷。我们假设 CI 缺陷引起的 NADH 积累会降低心脏功能 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提供了一条替代途径来消耗过量的NADH并形成FADH2以维持FA 氧化并防止氧化应激和 ATP 耗竭，同时保护心脏功能。第一个具体目标是 确定 NNT 是否有必要保护线粒体 CI 缺陷的心脏功能和结构。这 第二个具体目标是描述 NNT 在维持完整 FA β-氧化和 ATP 产生中的作用 CI 有缺陷的线粒体。第三个具体目标是破译 NNT 对氧化还原正常化的贡献 状态并减少 CI 缺陷线粒体的氧化应激。我们的具体目标与以下目标一致： 我们的研究治愈线粒体心肌病。我们将比较心脏、心肌细胞和 来自正常和缺失（全身和心脏特异性）CRISPR NNT 敲除小鼠的线粒体 C57BL6N 背景。鱼藤酮诱导的和类人 NDUFS4 缺陷的心脏特异性 CI 缺陷将 用过的。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。