The chaperone-binding activity of the mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress
Sandra Backes,
Yury S. Bykov,
Tamara Flohr,
Markus Räschle,
Jialin Zhou,
Svenja Lenhard,
Lena Krämer,
Timo Mühlhaus,
Chen Bibi,
Cosimo Jann,
Justin D. Smith,
Lars M. Steinmetz,
Doron Rapaport,
Zuzana Storchová,
Maya Schuldiner,
Felix Boos,
Johannes M. Herrmann
Affiliations
Sandra Backes
Cell Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Yury S. Bykov
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
Tamara Flohr
Cell Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Markus Räschle
Molecular Genetics, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Jialin Zhou
Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany
Svenja Lenhard
Cell Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Lena Krämer
Cell Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Timo Mühlhaus
Computational Systems Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Chen Bibi
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
Cosimo Jann
Genome Biology Unit, EMBL, Meyerhofstraße 1, 69117 Heidelberg, Germany; Department of Biology, Institute of Biochemistry, ETH Zürich, 8093 Zürich, Switzerland
Justin D. Smith
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Lars M. Steinmetz
Genome Biology Unit, EMBL, Meyerhofstraße 1, 69117 Heidelberg, Germany; Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Doron Rapaport
Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany
Zuzana Storchová
Molecular Genetics, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Maya Schuldiner
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
Felix Boos
Cell Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
Johannes M. Herrmann
Cell Biology, University of Kaiserslautern, 67663 Kaiserslautern, Germany; Corresponding author
Summary: Most mitochondrial proteins are synthesized as precursors in the cytosol and post-translationally transported into mitochondria. The mitochondrial surface protein Tom70 acts at the interface of the cytosol and mitochondria. In vitro import experiments identified Tom70 as targeting receptor, particularly for hydrophobic carriers. Using in vivo methods and high-content screens, we revisit the question of Tom70 function and considerably expand the set of Tom70-dependent mitochondrial proteins. We demonstrate that the crucial activity of Tom70 is its ability to recruit cytosolic chaperones to the outer membrane. Indeed, tethering an unrelated chaperone-binding domain onto the mitochondrial surface complements most of the defects caused by Tom70 deletion. Tom70-mediated chaperone recruitment reduces the proteotoxicity of mitochondrial precursor proteins, particularly of hydrophobic inner membrane proteins. Thus, our work suggests that the predominant function of Tom70 is to tether cytosolic chaperones to the outer mitochondrial membrane, rather than to serve as a mitochondrion-specifying targeting receptor.
