title: Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol.
abstract: Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Wrobel
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Topf
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Bragoszewski
authors.affiliation: Department of Biochemistry and Functional Proteomics, Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.|ZBSA Centre for Biological Systems Analysis, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wiese
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Sztolsztener
authors.affiliation: Department of Biochemistry and Functional Proteomics, Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Oeljeklaus
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Aksana
authors.initials: A
authors.lastname: Varabyova
authors.affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, 02-106 Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lirski
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Chroscicki
authors.affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Seweryn
authors.initials: S
authors.lastname: Mroczek
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Januszewicz
authors.affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dziembowski
authors.affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, 02-106 Warsaw, Poland.|Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Koblowska
authors.affiliation: Department of Biochemistry and Functional Proteomics, Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.|ZBSA Centre for Biological Systems Analysis, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Warscheid
authors.affiliation: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chacinska
mesh_terms: D003600:Cytosol / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D011498:Protein Precursors / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics; D059467:Transcriptome; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; D011498:Protein Precursors; D020543:Proteome; D029701:Saccharomyces cerevisiae Proteins; D046988:Proteasome Endopeptidase Complex