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5000名儿童出生有遗传性线粒体疾病，其中30-40％是复杂的 （CI）导致心肌病，心力衰竭和死亡的缺陷。大部分慢性病 （糖尿病，冠状动脉疾病，心力衰竭，衰老）形成线粒体CI缺陷，这是关键因素 促进疾病进展和心脏并发症。将CI缺陷与 心脏病包括能量不足，氧化应激和增加[NADH]。继承或获得， 线粒体CI缺陷无法治愈。我们提出了一个新型的治疗靶标，该靶标可保留心脏氧化。 线粒体心肌病中的代谢和功能。该项目的目的是确定是否是否 线粒体酶，烟酰胺核经氢化酶（NNT）是维持心脏脂肪的必要条件 在压力降低（NADH增加）的条件下，酸（FA）β氧化是由A引起的 线粒体CI缺陷。我们假设由CI缺陷引起的NADH积累会下降心脏 氧化代谢因此减少了FA氧化和ATP的产生，并诱导氧化应激。一个 完整的NNT提供了消耗多余NADH并形成FADH2的替代路线以保持FA 在保留心脏功能的同时，氧化并预防氧化应激和ATP部署。第一个具体目的是 确定NNT是否需要保护线粒体CI缺陷中的心脏功能和结构。 第二个具体目的是描述NNT在维持完全FAβ氧化和ATP产生中的作用 在CI有缺陷的线粒体中。第三个具体目的是破译NNT对氧化还原归一化的贡献 状态并减少CI缺陷线粒体中的氧化应激。我们的具体目标与目标 我们治愈线粒体心肌病的研究。我们将比较心脏，心肌细胞和 来自正常和缺乏（全身和心脏特异性）CRISPR NNT敲除的小鼠的线粒体 C57BL6N背景。烤烤鱼酮诱导的和类人类的NDUFS4缺陷心脏特异性CI缺陷将是 用过的。预期的结果将确定NNT是否是保存心脏氧化的潜在治疗靶标 线粒体心肌病的代谢和功能。