title: ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells.
abstract: Proteostasis is crucial for life and maintained by cellular chaperones and proteases. One major mitochondrial protease is the ClpXP complex, which is comprised of a catalytic ClpX subunit and a proteolytic ClpP subunit. Based on two separate observations, we hypothesized that ClpX may play a leading role in the cellular function of ClpXP. Therefore, we analyzed the effect of ClpX overexpression on a myoblast proteome by quantitative proteomics. ClpX overexpression results in the upregulation of markers of the mitochondrial proteostasis pathway, known as the "mitochondrial unfolded protein response" (UPRmt). Although this pathway is described in detail in Caenorhabditis elegans, it is not clear whether it is conserved in mammals. Therefore, we compared features of the classical nematode UPRmt with our mammalian ClpX-triggered UPRmt dataset. We show that they share the same retrograde mitochondria-to-nucleus signaling pathway that involves the key UPRmt transcription factor CHOP (also known as Ddit3, CEBPZ or GADD153). In conclusion, our data confirm the existence of a mammalian UPRmt that has great similarity to the C. elegans pathway. Furthermore, our results illustrate that ClpX overexpression is a good and simple model to study the underlying mechanisms of the UPRmt in mammalian cells.
authors.affiliation: Department of Medical Biochemistry and Biophysics, KBC, Kemihuset, University of Umeå, SE-90187 Umeå, Sweden; Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, D-61231 Bad Nauheim, Germany. Electronic address: Natalie.Al-Furoukh@umu.se.
authors.forename: Natalie
authors.initials: N
authors.lastname: Al-Furoukh
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, D-61231 Bad Nauheim, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ianni
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nolte
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, D-61231 Bad Nauheim, Germany.
authors.forename: Soraya
authors.initials: S
authors.lastname: Hölper
authors.affiliation: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Department of Medical Biochemistry and Biophysics, KBC, Kemihuset, University of Umeå, SE-90187 Umeå, Sweden.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Wanrooij
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, D-61231 Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
mesh_terms: D000818:Animals; D049071:Endopeptidase Clp / Q000096:biosynthesis* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D051742:Transcription Factor CHOP; C000589752:CLPP protein, mouse; C568646:ClpP protein, human; D049071:Endopeptidase Clp; C528384:CLPX protein, human; C000589753:CLPX protein, mouse
keywords: CHOP/Ddit3/CEBPZ/GADD153; ClpXP; Myogenesis; Proteomics; SILAC; UPR(mt) (mitochondrial unfolded protein response)