Regulation of mitochondrial biogenesis by cytosolic kinases

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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.