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Regulation of mitochondrial biogenesis by cytosolic kinases

胞质激酶对线粒体生物发生的调节

基本信息

批准号：
261328584
负责人：
Professor Dr. Chris Meisinger
金额：
--
依托单位：
Institut für Biochemie und Molekularbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/261328584?language=en
关键词：
Regulation mitochondrial biogenesis cytosolic kinases

项目摘要

Mitochondria are essential organelles in eukaryotic cells and perform a multitude of functions which are important for cell life and death. Most of the approx. 1000 (yeast) to 1500 (human) mitochondrial proteins are encoded in the nucleus and have to be imported into the organelle and sorted to their final destination in one of the four mitochondrial subcompartments. The TOM complex (translocase of the outer membrane) serves here as the central protein entry gate from where preproteins are delivered to further intramitochondrial import and sorting machineries. We have performed detailed structural and functional analyses of the TOM complex, discovered the SAM complex as a novel protein sorting and assembly machinery in the outer membrane and uncovered a role of components of the ER-mitochondria encounter structure (ERMES), which links mitochondria to ER membranes, in protein biogenesis. So far it was largely unknown if mitochondrial protein biogenesis can be regulated by posttranslational modifications. Based on our discovery of an unexpectedly high number of phosphorylation sites of mitochondrial outer membrane proteins and the identification of cytosolic kinases that regulate protein import into mitochondria, we propose the hypothesis that the mitochondrial outer membrane may serve as a general signal integration platform that mediates communication between mitochondria and other cellular compartments. Several TOM phosphorylation sites appear to be targets of cyclin-dependent kinases and MAP kinases. We will therefore investigate the link between mitochondrial protein import and cell cycle regulation and study the role of the protein import machinery during the various cell cycle phases. Such a link will offer a highly exciting and novel basis for understanding how mitochondrial biogenesis is embedded into cell cycle regulation pathways. Moreover we will analyze the role of phosphorylation of the various ERMES components and dissect its role in protein biogenesis, lipid transport and morphology. We will identify ERMES kinases and study signalling pathways that regulate the formation of physical interorganellar contact sites by phosphorylation.

线粒体是真核细胞中必不可少的细胞器，并执行对细胞生死至关重要的多种功能。大部分的接近。1000（酵母）至1500（人类）线粒体蛋白质在细胞核中编码，必须输入细胞器并在四个线粒体亚区之一中分类到其最终目的地。TOM复合物（外膜的转位酶）在这里作为中央蛋白质入口门，前蛋白从这里被递送到进一步的线粒体内输入和分选机器。我们已经进行了详细的结构和功能分析的TOM复合物，发现SAM复合物作为一种新的蛋白质分选和装配机械的外膜和发现的ER-线粒体遇到结构（ERMES），连接线粒体的ER膜，在蛋白质生物合成的组件的作用。到目前为止，很大程度上是未知的，如果线粒体蛋白质的生物合成可以通过翻译后修饰。基于我们发现的线粒体外膜蛋白的磷酸化位点的数量出乎意料的高，并确定调节蛋白质输入线粒体的胞质激酶，我们提出的假设，线粒体外膜可能作为一个一般的信号整合平台，介导线粒体和其他细胞室之间的通信。几个TOM磷酸化位点似乎是细胞周期蛋白依赖性激酶和MAP激酶的靶点。因此，我们将研究线粒体蛋白质进口和细胞周期调控之间的联系，并研究蛋白质进口机制在细胞周期的各个阶段的作用。这种联系将为理解线粒体生物合成如何嵌入细胞周期调控途径提供一个非常令人兴奋和新颖的基础。此外，我们将分析各种ERMES组分的磷酸化作用，并剖析其在蛋白质生物合成，脂质转运和形态学中的作用。我们将鉴定ERMES激酶并研究通过磷酸化调节物理细胞器间接触位点形成的信号通路。