title: Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.
abstract: The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans Far less is known about mammalian UPR(mt) signaling, although similar roles were assumed for central players, including CLPP To better understand the mammalian UPR(mt) signaling, we deleted CLPP in hearts of DARS2-deficient animals that show robust induction of UPR(mt) due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR(mt) in mammals. Surprisingly, we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPR(mt) signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Seiferling
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Szczepanowska
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Becker
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Senft
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hermans
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Priyanka
authors.identifier: 0000-0003-4207-0341
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: König
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kukat
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany aleksandra.trifunovic@uk-koeln.de.
authors.forename: Aleksandra
authors.identifier: 0000-0002-5472-3517
authors.initials: A
authors.lastname: Trifunovic
mesh_terms: D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000172:deficiency; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049071:Endopeptidase Clp / Q000172:deficiency*; D005260:Female; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D024101:Mitochondrial Proteins; C000589752:CLPP protein, mouse; C568646:ClpP protein, human; D049071:Endopeptidase Clp; D001226:Aspartate-tRNA Ligase
keywords: CLPP; DARS2; cardiomyopathy; mitochondrial translation; mitochondrial unfolded protein response