Regulation of mitochondrial morphology and functional versatility

项目总结 真核细胞将关键的生化反应隔离到离散的膜室中，从而 由蛋白质催化剂驱动的膜动力学促进分化、交流和空间组织 细胞内的隔间。在细胞内，线粒体主要被组织成高度相互连接的 网络的不同功能依赖于其复杂的结构和组织。在人类中，OPA1 和MICOS是基本的生物分子机器，不仅控制线粒体的形态 还有许多关键的线粒体过程的效率，包括氧化磷酸化， 代谢、细胞凋亡和线粒体DNA维持。GTP酶OPA1对线粒体IM融合和 调节脊骨动力学，而多组分MICOS复合体通过塑造IM起双重作用 冠状连接，与外膜形成接触部位。描述线粒体动力学如何 对于破译线粒体形态和线粒体之间的联系是至关重要的 功能。此外，线粒体动力学中的分子异常导致线粒体结构异常， 生物能量学受损，呼吸能力严重下降，线粒体DNA不稳定，对 细胞凋亡和各种疾病的发展，包括神经退行性疾病， 各种癌症、肥胖症和心血管疾病。然而，改变线粒体的分子机制 其形态和功能尚不完全清楚。在这里，使用细胞和结构的组合 分析，我们的目标是发展对线粒体动力学的分子理解，这些动力学支配着关键的生理 细胞内的过程。我们建议通过以下方法来确定线粒体形态发生的分子机制 探讨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)。 我们进一步提出了表征多组分MICOS络合物和蛋白质的分子细节 促进脊骨形成和维持线粒体的特征结构的动力学(目标2)。 对线粒体蛋白质机器的结构和功能的研究将提供一个平台，以确定 与人类疾病和年龄相关疾病有关的病理学。理解精确的分子机制 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几率。

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.