Regulation of mitochondrial morphology and functional versatility

线粒体形态和功能多样性的调节

• 批准号: 10715704
• 负责人: HALIL AYDIN
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715704
• 关键词: Apoptosis; Architecture; Biochemical Reaction; Bioenergetics; Cardiolipins; Cardiovascular Diseases; Cell division; Cell physiology; Cells; Characteristics; Communication; Complex; Crista ampullaris; Development; Disease; Eukaryotic Cell; Guanosine Triphosphate Phosphohydrolases; Human; Impairment; Knowledge; Link; Lipids; Maintenance; Malignant Neoplasms; Membrane; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Molecular; Molecular Abnormality; Morphogenesis; Morphology; Muscle; Neurodegenerative Disorders; Neurons; OPA1 gene; Obesity; Organelles; Oxidative Phosphorylation; Pathology; Physiological Processes; Play; Probability; Process; Protein Dynamics; Proteins; Regulation; Reticulum; Role; Shapes; Site; Spatial Distribution; Structure; age related; catalyst; environmental change; human disease; migration; mitochondrial dysfunction; novel therapeutic intervention; respiratory; success

PROJECT SUMMARY Eukaryotic cells sequester critical biochemical reactions into discrete membranous compartments, whereby membrane dynamics driven by protein catalysts facilitate differentiation, communication, and spatial organization of intracellular compartments. Within a cell, mitochondria are mainly organized into highly interconnected networks, whose diverse functions are dependent on their complex structure and organization. In humans, OPA1 and MICOS are essential biomolecular machines that control not only the morphology of the mitochondrial reticulum, but also the efficiency of many key mitochondrial processes, including oxidative phosphorylation, metabolism, apoptosis, and mtDNA maintenance. The GTPase OPA1 is crucial for mitochondrial IM fusion and regulating cristae dynamics, whereas the multi-component MICOS complex plays a dual role by shaping IM cristae junctions and forming contact sites with the outer membrane. Characterizing how mitochondrial dynamics are realized and regulated will be essential to deciphering the link between mitochondrial morphology and function. Moreover, molecular abnormalities in mitochondrial dynamics result in aberrant mitochondrial structure, impaired bioenergetics, severely reduced respiratory capacity, mtDNA instability, increased sensitivity to apoptosis, and development of a wide variety of disease conditions, including neurodegenerative disorders, diverse cancers, obesity, and cardiovascular diseases. Yet, the molecular mechanisms that alter mitochondrial morphology and function remain incompletely understood. Here, using a combination of cellular and structural analyses, we aim to develop a molecular understanding of mitochondrial dynamics that govern key physiological processes in cells. We propose to determine the molecular mechanism of mitochondrial morphogenesis by exploring the assembly mechanism of OPA1 and its interactions with the mitochondrial lipid cardiolipin (Aim 1). We further propose to characterize the molecular details of multi-component MICOS complex and protein dynamics that facilitate cristae formation and maintain the characteristic architecture of mitochondria (Aim 2). Structural and functional studies of mitochondrial protein machines will provide a platform to identify the basis of pathologies linked to human disease and age-related illness. Understanding the precise molecular mechanisms of mitochondrial dynamics will increase the probability of success in developing new therapeutic interventions.

项目概要 真核细胞将关键的生化反应隔离在离散的膜区室中，从而 由蛋白质催化剂驱动的膜动力学促进分化、通讯和空间组织 细胞内区室。在细胞内，线粒体主要组织成高度互连的 网络的多样化功能取决于其复杂的结构和组织。在人类中，OPA1 和 MICOS 是重要的生物分子机器，不仅控制线粒体的形态 网状结构，还影响许多关键线粒体过程的效率，包括氧化磷酸化， 代谢、细胞凋亡和 mtDNA 维持。 GTPase OPA1 对于线粒体 IM 融合至关重要 调节嵴动力学，而多组分 MICOS 复合物通过塑造 IM 发挥双重作用 嵴连接处并与外膜形成接触位点。表征线粒体动力学 的实现和调节对于破译线粒体形态与线粒体之间的联系至关重要 功能。此外，线粒体动力学的分子异常导致线粒体结构异常， 生物能受损、呼吸能力严重下降、mtDNA 不稳定、对物质的敏感性增加 细胞凋亡和多种疾病的发展，包括神经退行性疾病， 多种癌症、肥胖症和心血管疾病。然而，改变线粒体的分子机制 形态和功能仍不完全清楚。在这里，结合使用细胞和结构 通过分析，我们的目标是对控制关键生理的线粒体动力学建立分子理解 细胞中的过程。我们建议通过以下方式确定线粒体形态发生的分子机制 探索 OPA1 的组装机制及其与线粒体脂质心磷脂的相互作用（目标 1）。 我们进一步建议表征多组分 MICOS 复合物和蛋白质的分子细节 促进嵴形成并维持线粒体特征结构的动力学（目标 2）。 线粒体蛋白质机器的结构和功能研究将提供一个平台来确定线粒体蛋白质机器的基础 与人类疾病和年龄相关疾病有关的病理学。了解精确的分子机制 线粒体动力学的研究将增加开发新的治疗干预措施的成功可能性。