Regulation of Mitochondrial Inner Membrane Organization

项目摘要/摘要 拟议的工作将提供培训，以支持候选人学习的长期职业目标 心肌细胞线粒体超微结构的分子机制。线粒体组织是 在心脏中尤其重要，因为线粒体呼吸产生了所需的大量能量 对心脏功能的影响。线粒体的形态和功能是紧密相连的； 在一些心肌病和老年心脏组织中的异常结构。线粒体内部 膜(IMM)横向上被组织成不同的功能域和形态域。然而， 在心脏和其他细胞中IMM组织的分子机制在很大程度上是未知的。在这方面， 这项建议的研究目标是理解指导的基本分子原理所必需的 线粒体结构组织。MICOS复合体组织了海脊连接(CJ)，即沿 IMM描绘了生物发生和呼吸机制所在的边界和脊区， 分别进行了分析。MICOS对于调节CJ的拷贝数和定位以及MICOS中的突变至关重要 导致呼吸功能下降。然而，作为MICOS组装和基础的机制 监管并没有得到很好的理解。为了解决这些不足，候选人将确定以下基础 MICOS亚基Mic60和Mic19的分子作用(特定目标1)。这些蛋白质是假想的， 根据应聘者以前的工作，确定CJ的副本数量和位置。拟议的工作将 也采取候选和前瞻性的方法来确定MICOS功能的调节机制 (具体目标2和3)。在提案的K99阶段，候选人将接受蛋白质方面的培训 生物化学分析和系统生物学方法将促进实现上述每一项 独立阶段的研究目标。应聘者在细胞器生物学方面有很强的背景 应聘者的机构和导师实验室培训环境是世界级的，并满足 满足候选人的培训需求，使这项提案的短期和长期目标都可以实现。 确定指导IMM组织的分子原理将使候选人能够专注于眉骨 对心脏的调节，并确定治疗心脏病的潜在治疗方法，这 将成为未来赠款申请的基础。

Project Summary/Abstract The proposed work will provide training to support the candidate's long-term career goal of studying the molecular mechanisms underpinning mitochondrial ultrastructure in cardiac cells. Mitochondrial organization is particularly critical in the heart, as mitochondrial respiration generates the massive amount of energy required for cardiac function. Mitochondrial form and function are intimately linked; cristae, the site of respiration, form aberrant structures in a number of cardiomyopathies and in aged cardiac tissues. The mitochondrial inner membrane (IMM) is laterally organized into distinct functional and morphological domains. However, the molecular mechanisms of IMM organization in cardiac and other cells are largely unknown. In this context, the research goals of this proposal are necessary to understand the basic molecular principles guiding mitochondrial architectural organization. The MICOS complex organizes cristae junctions (CJs), sites along the IMM that delineate the boundary and cristae domains, which house biogenesis and respiratory machinery, respectively. MICOS is critical for regulating the copy number and positioning of CJs and mutations in MICOS lead to a reduction of respiratory function. However, the mechanisms that underlie MICOS assembly and regulation are not well understood. To address these deficits, the candidate will determine the basis of molecular action of the MICOS subunits Mic60 and Mic19 (Specific Aim 1). These proteins are hypothesized, based on the candidate's prior work, to determine CJ copy number and placement. The proposed work will also take candidate and forward approaches to determine mechanisms of regulation of MICOS function (Specific Aims 2 and 3). During the K99 phase of the proposal, the candidate will be trained in protein biochemical analyses and systems biology approaches that will promote the accomplishment of each of these research goals during the independent phase. The candidate has a strong background in organelle biology and the institutional and mentor laboratory training environments of the candidate are world-class and meet the training needs of the candidate, making the short-term and long-term goals of this proposal attainable. Determining the molecular principles guiding IMM organization will enable the candidate to focus on cristae regulation in the heart and identify potential therapeutic approaches for the treatment of cardiac disease, which will be the basis of future grant applications.