Mitochondrial Precursor Proteins in the Cytosol: Identification and Characterization of Signals and Factors that Coordinate Early Steps in Mitochondrial Protein Biogenesis
Final Report Abstract
Mitochondria are essential organelles of eukaryotic cells. They consist of 800 to 1500 proteins, most of which are synthesized in the cytosol as precursor proteins. Little is known about the reactions in the cytosol by which precursor proteins are maintained in an unfolded, import-competent form, targeted to the mitochondria, recognized by surface receptors and sorted into the specific mitochondrial subcompartments. These early processes of mitochondrial protein targeting are under surveillance of the proteasome system in order to avoid the accumulation of non-imported precursor proteins in the cytosol, but details are largely elusive. In this project, we addressed two related questions: In the first objective, we elucidated the features of the mitochondrial precursor proteins that determine their (mis)folding in the cytosol and their targeting to mitochondria. We analyzed the specific relevance of internal signals within the mature parts of mitochondrial proteins. These internal matrix targeting signal-like sequences (iMTS-Ls) bind to the mitochondrial surface receptor Tom70 and increase the import efficiency of proteins. Tom70 serves as a recruitment factor for chaperones that increases the local chaperone concentration on the mitochondrial surface. This function of Tom70 is apparently the main role of this receptor in vivo, and the replacement of Tom70 by another chaperone-binding factor almost fully complemented Tom70- deficient cells. The second goal of this project was to understand the biological reactions that are induced if mitochondrial precursor proteins accumulate in the cytosol. In the past, we have observed that increased levels of these precursors induced a strong cellular stress response causing the upregulation of chaperones and of components of the proteolytic system of the cytosol. We now discovered a novel cellular strategy by which cells protect the cytosol against mitochondrial precursor proteins. Using the small heat shock protein Hsp42 as a nucleation factor, the cytosol induces the formation of aggregates which sequester accumulating precursors. We named these structures MitoStores as they store precursor proteins transiently and release them once the stress conditions are over. From our studies we gained detailed insights into the reactions that regulate the early steps in mitochondrial protein biogenesis, either by stimulating the efficient import of precursor proteins into mitochondria (objective 1) or by removing accumulating precursor proteins by the cytosolic quality control system (objective 2).
Publications
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More than just a ticket canceller: the mitochondrial processing peptidase tailors complex precursor proteins at internal cleavage sites. Molecular Biology of the Cell, 31(24), 2657-2668.
Friedl, Jana; Knopp, Michael R.; Groh, Carina; Paz, Eyal; Gould, Sven B.; Herrmann, Johannes M. & Boos, Felix
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Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol. The EMBO Journal, 40(16).
Schlagowski, Anna M.; Knöringer, Katharina; Morlot, Sandrine; Sánchez, Vicente Ana; Flohr, Tamara; Krämer, Lena; Boos, Felix; Khalid, Nabeel; Ahmed, Sheraz; Schramm, Jana; Murschall, Lena M.; Haberkant, Per; Stein, Frank; Riemer, Jan; Westermann, Benedikt; Braun, Ralf J.; Winklhofer, Konstanze F.; Charvin, Gilles & Herrmann, Johannes M.
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The chaperone-binding activity of the mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress. Cell Reports, 35(1), 108936.
Backes, Sandra; Bykov, Yury S.; Flohr, Tamara; Räschle, Markus; Zhou, Jialin; Lenhard, Svenja; Krämer, Lena; Mühlhaus, Timo; Bibi, Chen; Jann, Cosimo; Smith, Justin D.; Steinmetz, Lars M.; Rapaport, Doron; Storchová, Zuzana; Schuldiner, Maya; Boos, Felix & Herrmann, Johannes M.
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The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import. Life Science Alliance, 6(1), e202201526.
Rödl, Saskia; den, Brave Fabian; Räschle, Markus; Kizmaz, Büsra; Lenhard, Svenja; Groh, Carina; Becker, Hanna; Zimmermann, Jannik; Morgan, Bruce; Richling, Elke; Becker, Thomas & Herrmann, Johannes M.
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Mitochondrial dysfunction rapidly modulates the abundance and thermal stability of cellular proteins. Life Science Alliance, 6(6), e202201805.
Groh, Carina; Haberkant, Per; Stein, Frank; Filbeck, Sebastian; Pfeffer, Stefan; Savitski, Mikhail M.; Boos, Felix & Herrmann, Johannes M.
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MitoStores: chaperone‐controlled protein granules store mitochondrial precursors in the cytosol. The EMBO Journal, 42(7).
Krämer, Lena; Dalheimer, Niko; Räschle, Markus; Storchová, Zuzana; Pielage, Jan; Boos, Felix & Herrmann, Johannes M.
