The interplay between endoplasmic reticulum and mitochondria in protein targeting and mistargeting

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Eukaryotic cells are divided into distinct compartments each with their own defining set of proteins. A fundamental problem in molecular cell biology is to understand how proteins that are synthesized on cytosolic ribosomes reach their respective intracellular address. Recent studies by us and others demonstrated that such targeting processes occur under surveillance of stringent quality control measures and can be revised and corrected in cases where a protein was mislocalized to an inappropriate location. Maintaining the precise organellar proteome is especially demanding in the case of mitochondria and the endoplasmic reticulum (ER). These two compartments are intertwined in an elaborate array of physical contacts, multifold exchange reactions for metabolites, lipids and common resident proteins, and interconnected stress response pathways. The biogenesis of newly synthesized mitochondrial and ER proteins relies on a fine balance of targeting to, integration into, as well as extraction from membranes of both organelles, a complex interplay that, despite its importance, is largely uncharacterized. In this collaborative project, we will combine the complementing expertise of three groups to elucidate the role of the ER for the biogenesis of mitochondrial proteins. For this project, we will study the three conceptually distinct functions of the ER surface for the targeting of mitochondrial proteins in three distinct work packages, each spearheaded by one group but dependent on the close collaboration of all three: Led by the Herrmann group we will study how the ER surface can support the productive targeting of precursor proteins to mitochondria through the process of ER-SURF that we have recently discovered. We will define the substrate repertoire and the molecular mechanisms of the ER-SURF pathway. Led by the Rapaport group, we will study which mitochondrial precursors get mistargeted and how these proteins can be recovered or degraded, a problem which particularly arises for outer membrane proteins. Led by the Schuldiner group we will identify the dual localized proteins which form permanent residents of both the ER and mitochondria and elucidate the molecular features underlying the regulated targeting of these proteins to both destinations. For these three aims, we will use bakers’ yeast as a model organism and combine the powerful approaches that are the expertise of each lab - high throughput genetic screens, fluorescence microscopy, biochemistry and physiological assays. The success of the proposed project is clearly dependent on the tight collaboration of all three participating groups – proven over the last decade to be a powerful combination. Collectively, this collaborative, timely, and innovative project will allow us to unravel the exciting, and so far largely uncharacterized, early reactions in mitochondrial protein targeting.