Mechanisms of Mitochondrial Ultrastructural Changes and Metabolic Dysfunction Caused by Calcium Overload

钙超载引起线粒体超微结构变化和代谢功能障碍的机制

• 批准号: 10383137
• 负责人: Jasiel Omil Strubbe
• 金额: $ 3.1万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-16 至 2023-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383137
• 关键词: ATP Synthesis Pathway; Academic skills; Address; Award; Biochemical; Bioenergetics; Biological Assay; Buffers; Calcium; Cardiac; Cardiovascular Diseases; Cavia; Cell Death; Cell physiology; Clinical; Clinical Trials; Communication; Consequentialism; Coupled; Crista ampullaris; Cryoelectron Microscopy; Cytoplasmic Granules; Data; Development; Disease; Drug Targeting; Educational workshop; Energy Metabolism; Fellowship; Functional disorder; Grant; Health; Heart; Heart Diseases; Image; Impairment; Individual; Injury; Inner mitochondrial membrane; Institution; Knowledge; Lead; Link; Location; Manuscripts; Measures; Mediating; Membrane; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Mitochondrial Diseases; Molecular; Myocardial Infarction; Myocardial Ischemia; Nature; Outcome; Pathologic; Pathway interactions; Perfusion; Pharmacologic Substance; Physiological; Physiology; Play; Prevention; Process; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Resolution; Scientist; Shapes; Structure; System; Testing; Tissues; Training; Work; Writing; calcium phosphate; improved; innovation; insight; mitochondrial dysfunction; novel therapeutic intervention; novel therapeutics; posters; preservation; prevent; success; symposium; targeted treatment; therapeutic target; treatment strategy; uptake

Project Summary/Abstract: Myocardial ischemia/reperfusion (IR) is an injury preceded by mitochondrial dysfunction caused by calcium overload. While mitochondrial calcium dynamics and molecular pathways have been extensively studied, little is known on how mitochondria accumulate and store calcium and how calcium overload effects mitochondrial function. This is significant since the main cause of cardiac tissue and cell death after a myocardial infarction is mediated by mitochondrial calcium overload. As there are no adequate treatments available, the nature of calcium storage and its impact on mitochondrial function requires further study. Herein, we show preliminary results that reveal an unprecedented link between cristae structure and mitochondrial function during calcium overload. The presented data suggest that preserving cristae during calcium overload confer protection against calcium overload. Confirming this hypothesis will add an exciting new therapeutic approach and puts in immediate play proteins not considered as drug targets to treat IR injury. The objectives of this proposal are 1) to characterize and quantify the calcium sequestration system and the direct effects on mitochondrial function, 2) to determine the functional impact of cristae remodeling in mitochondria ultrastructure associated with calcium overload, and 3) establish how known modulators of the calcium sequestration system alter mitochondrial function. The experimental approach in this proposal will use recent methods of advanced cryo- EM, spectrofluorimetry, ex vivo heart perfusion system, and high-resolution respirometry. Bioenergetic and functional data will be measured from isolated cardiac mitochondria from healthy, ischemic, and IR injured guinea pig hearts. In addition, support from this fellowship will be directed to acquire experimental and academic skills sets that are key to the proposal success. These will be approached by taking high-quality courses offered at MSU, hands-on training, workshops, and regional and national conferences. Gathering scientific expertise via the F31 Award in mitochondria and cellular physiology will provide opportunities for improving scientific communication through talks, posters, and manuscript writing. The opportunity granted via the F31 Award will continue and expand this work to encompass the bioenergetic consequences between mitochondrial calcium overload and mitochondrial ultrastructure related to a pathophysiological scenario such as IR injury. The combined efforts of the fellowship award, extensive expertise of sponsors, co-sponsors, collaborator, and the institution’s commitment to excellence is an optimal pathway to independence that will help unlock the potential as a successful scientist.

项目概要/摘要： 心肌缺血/再灌注（IR）是一种由钙离子介导的线粒体功能障碍引起的损伤 超载。虽然线粒体钙动力学和分子途径已被广泛研究， 线粒体如何积累和储存钙以及钙超载如何影响线粒体 功能这是重要的，因为心肌梗死后心脏组织和细胞死亡的主要原因是 由线粒体钙超载介导。由于没有足够的治疗方法， 钙储存及其对线粒体功能的影响需要进一步研究。在这里，我们展示了初步的 这些结果揭示了在钙代谢过程中嵴结构和线粒体功能之间前所未有的联系， 超载。所提供的数据表明，在钙超载期间保留嵴可保护 钙超载证实这一假设将增加一个令人兴奋的新的治疗方法， 不被认为是治疗IR损伤的药物靶点的直接作用蛋白。本提案的目标 是1）表征和量化钙螯合系统和对线粒体的直接影响 功能，2）确定线粒体超微结构中嵴重塑相关的功能影响 与钙超载，和3）建立如何已知的调节剂的钙螯合系统改变 线粒体功能该提案中的实验方法将使用最新的先进冷冻方法， EM、荧光光谱法、离体心脏灌注系统和高分辨率呼吸测定法。生物能量和 将从健康、缺血和IR损伤的分离的心脏线粒体测量功能数据 豚鼠心脏此外，该研究金的支助将用于获得实验性和 学术技能是成功的关键。这些将通过采取高质量的 密歇根州立大学提供的课程、实践培训、讲习班以及区域和国家会议。收集 通过F31奖在线粒体和细胞生理学方面的科学专业知识将为以下方面提供机会： 通过演讲、海报和手稿写作改善科学交流。通过以下途径获得的机会 “F31奖”将继续并扩大这项工作，以涵盖以下两个方面的生物能成果： 线粒体钙超载和线粒体超微结构相关的病理生理情况， IR损伤。研究金的共同努力，赞助者、共同赞助者的广泛专门知识， 合作者，该机构对卓越的承诺是实现独立的最佳途径， 帮助释放成为一名成功科学家的潜力。