Regulation of mitochondrial inner membrane organization

线粒体内膜组织的调节

• 批准号: 9606265
• 负责人: Jonathan R. Friedman
• 金额: $ 24.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9606265
• 关键词: Address; Antimycin A; Applications Grants; Architecture; Binding Sites; Biochemical; Biogenesis; Biological Assay; Biology; CRISPR interference; Cardiac; Cardiomyopathies; Cell physiology; Cells; Collaborations; Complex; Crista ampullaris; Data; Disease; Environment; Fluorescence Microscopy; Future; Generations; Genes; Genetic; Goals; Heart; Heart Diseases; Human; Inner mitochondrial membrane; Lead; Link; Maps; Mediating; Membrane; Mentors; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Morphogenesis; Morphology; Mutation; Organelles; Peptide Hydrolases; Phase; Play; Positioning Attribute; Production; Protein Complex Subunit; Proteins; Proteomics; Publishing; Quality Control; Regulation; Research; Respiration; Respiratory physiology; Role; Site; Structure; Systems Biology; Testing; Therapeutic; Tissues; Training; Work; Yeasts; aged; base; career; genome wide screen; genome-wide; heart function; in vivo; inhibitor/antagonist; laboratory experience; new therapeutic target; novel; respiratory; self assembly; therapeutic development

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.

项目总结/摘要 拟议的工作将提供培训，以支持候选人的长期职业目标， 心肌细胞线粒体超微结构的分子机制。线粒体组织是 这在心脏中尤其重要，因为线粒体呼吸产生所需的大量能量。 心脏功能。线粒体的形式和功能是密切相关的;嵴，呼吸的网站，形式 许多心肌病和老年心脏组织中的异常结构。线粒体内部 膜（IMM）横向组织成不同的功能和形态结构域。但 在心脏和其它细胞中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必要的，以了解基本的分子原理指导 线粒体结构MICOS复合体组织嵴连接（CJ），沿着 IMM描绘了边界和嵴域，其中容纳生物发生和呼吸机制， 分别MICOS对于调节拷贝数和CJ的定位以及MICOS中的突变至关重要 导致呼吸功能降低。然而，作为MICOS组装和 规则并没有得到很好的理解。为了解决这些缺陷，候选人将确定 MICOS亚基Mic 60和Mic 19的分子作用（特异性目的1）。假设这些蛋白质， 根据候选人之前的工作，以确定CJ拷贝数和位置。拟议的工作将 还采取候选和前瞻性方法来确定MICOS功能的调节机制 （具体目标2和3）。在K99阶段，候选人将接受蛋白质培训 生物化学分析和系统生物学方法，将促进实现每一个这些 独立阶段的研究目标。候选人在细胞器生物学方面有很强的背景， 候选人的机构和导师实验室培训环境是世界一流的，并符合 候选人的培训需求，使本提案的短期和长期目标得以实现。 确定指导IMM组织的分子原则将使候选人能够专注于Cristae 调节，并确定治疗心脏病的潜在治疗方法， 将成为今后申请资助的基础。