Remodeling mitochondrial cristae to rescue bioenergetic defects in mitochondrial disease

项目摘要 线粒体根据细胞的生理状态调整其形状并影响细胞代谢 牢房。脊是线粒体的动态隔膜，它通过以下方式决定其生物能量能力 氧化磷酸化(OXPHOS)反应动力学及其结构调控 复合体。包括线粒体在内的许多病理条件下，脊骨的形状都受到调节。 无法治愈的疾病。在这里，眉骨重塑背后的分子机制将是 研究通过联合治疗线粒体疾病中观察到的生物能量缺陷 超微结构、生化和生物能分析。 普伊格瑟尔实验室已经表明，内质网应激反应的一个组成部分，R(PKR)样的内质网激酶 (PERK)，重塑眉骨，并通过调节能量转移促进线粒体呼吸 ElF2α-ATF4轴。在眉骨形成的背景下，内质网和线粒体之间的通讯是 这是一个相对勘探不足的地区，对这种串扰的监管尚不清楚。这项提案调查了一个 PERK通路在线粒体疾病中挽救脊形变中的新作用。目标1侧重于 PERK的下游效应以及线粒体的代谢组和蛋白质组特征如何 改变以挽救在OXPHOS复合体I缺陷细胞中看到的生物能量缺陷。目标2描述了 内质网-线粒体接触部位在PERK介导的骨脊形成中的作用。《目标3》探索 附加的激酶，如已知的在不同类型的压力下使elF2α磷酸化的Perk， 以及它们在修复线粒体突变体的生物能缺陷方面的潜在作用。 Puigserver是Dana Farber癌症研究所和哈佛大学一个充满活力的研究社区的一部分 医学院，拥有成熟的工具、细胞系和方法来探索线粒体新陈代谢 并进行所有提议的实验。这些研究希望确定和探索新的途径， 调整脊骨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.