Regulation of mitochondrial biogenesis by cytosolic kinases

线粒体是真核细胞中必不可少的细胞器，对细胞的生死起着重要的作用。大部分的近似。1000个（酵母）到1500个（人类）线粒体蛋白在细胞核中编码，必须输入细胞器，并在四个线粒体亚室之一中分类到最终目的地。TOM复合体（外膜转位酶）在这里作为中心蛋白入口，从这里将前蛋白传递到进一步的线粒体内进口和分选机制。我们对TOM复合体进行了详细的结构和功能分析，发现SAM复合体是外膜中一种新的蛋白质分选和组装机制，并揭示了连接线粒体和内质网膜的ER-线粒体相遇结构（ERMES）成分在蛋白质生物发生中的作用。到目前为止，线粒体蛋白的生物发生是否可以通过翻译后修饰来调节，这在很大程度上是未知的。基于我们意外发现的线粒体外膜蛋白磷酸化位点的数量和调节蛋白质进入线粒体的胞质激酶的鉴定，我们提出了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区室之间的通信的假设。几个TOM磷酸化位点似乎是周期蛋白依赖性激酶和MAP激酶的靶标。因此，我们将研究线粒体蛋白质进口与细胞周期调节之间的联系，并研究蛋白质进口机制在不同细胞周期阶段的作用。这种联系将为理解线粒体生物发生如何嵌入细胞周期调节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成分的磷酸化作用，并剖析其在蛋白质生物发生，脂质转运和形态中的作用。我们将鉴定ERMES激酶并研究通过磷酸化调节物理胞间接触位点形成的信号通路。

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.