Remodeling mitochondrial cristae to rescue bioenergetic defects in mitochondrial disease

项目摘要 线粒体适应它们的形状并影响细胞代谢，以响应细胞的生理状态。 牢房嵴是脊椎骨的动态隔间，通过以下方式决定其生物能量能力： 调节氧化磷酸化（OXPHOS）反应的动力学和OXPHOS的结构 配合物嵴的形状在许多病理条件下，包括线粒体 无法治愈的疾病在这里，嵴重塑的分子机制将是 研究通过结合以下方法来挽救在线粒体疾病中观察到的生物能量缺陷： 超微结构、生物化学和生物能量分析。 Puigserver实验室已经表明，ER应激反应的一个组成部分，R（PKR）样ER激酶， （PERK），重塑嵴，并介导一个充满活力的转变，以促进线粒体呼吸，通过 elf2 α-ATF4轴。在嵴形成的背景下，内质网和线粒体之间的通讯是 这是一个相对开发不足的领域，并且这种串扰的调节尚不清楚。该提案调查了 PERK通路在线粒体疾病期间挽救嵴形状中的新作用。目标1侧重于 PERK的下游效应以及线粒体的代谢组学和蛋白质组学特征是如何 改变以拯救在OXPHOS复合物I缺陷细胞中观察到的生物能量缺陷。目标2描述了 ER-线粒体接触位点对PERK介导的嵴形成的贡献。Aim 3探索 另外的激酶如PERK，已知其响应于不同类型的应激而磷酸化elf 2 α， 以及它们在挽救线粒体突变体中的生物能量缺陷中的潜在作用。 Puigserver是Dana Farber癌症研究所和哈佛的动态研究社区的一部分 医学院，与既定的工具，细胞系和方法，探索线粒体代谢 并执行所有提议的实验。这些研究希望确定和探索新的途径， 调节嵴的形状，以挽救与线粒体疾病相关的生物能量缺陷。

Project Summary Mitochondria adapt their shape and influence cellular metabolism in response to the physiological state of the cell. Cristae are dynamic compartments of the mitochondrion that dictate its bioenergetic capacity by regulating the kinetics of Oxidative Phosphorylation (OXPHOS) reactions and the structure of the OXPHOS complexes. Cristae shape is regulated during many pathological conditions, including mitochondrial diseases with no available cure. Here, the molecular mechanisms that underlie cristae remodeling will be investigated to rescue bioenergetic defects observed in mitochondrial disorders by combining ultrastructural, biochemical and bioenergetic analyses. The Puigserver Lab has shown that a component of the ER stress response, R(PKR)-like ER kinase (PERK), remodels cristae and mediates an energetic shift to promote mitochondrial respiration through the elf2α-ATF4 axis. The communication between the ER and mitochondria in the context of cristae formation is a relatively under-explored area and the regulation of this cross-talk is unclear. This proposal investigates a novel role for the PERK pathway in rescuing cristae shape during mitochondrial disease. Aim 1 focuses on the downstream effects of PERK and how the metabolomic and proteomic signatures of mitochondria are altered to rescue bioenergetic defects seen in OXPHOS Complex I deficient cells. Aim 2 characterizes the contribution of the ER-mitochondria contact sites to PERK mediated cristae formation. Aim 3 explores additional kinases like PERK that are known to phosphorylate elf2α in response to different types of stress, and their potential role in rescuing bioenergetic defects in mitochondrial mutants. The Puigserver is part of a dynamic research community at the Dana Farber Cancer Institute and Harvard Medical School, with established tools, cell lines and methodologies to explore mitochondrial metabolism and perform all the proposed experiments. These studies hope to identify and explore new pathways that regulate cristae shape to rescue bioenergetic defects associated with mitochondrial disease.