title: Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice.
abstract: Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure. Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Feeding mice a high-fat diet or ablating Yme1l in skeletal muscle restored cardiac metabolism and preserved heart function without suppressing mitochondrial fragmentation. Thus, unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Max-Planck-Institute for Biology of Aging, Cologne, Germany.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wai
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: García-Prieto
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Baker
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Merkwirth
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, Paris, France. Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Benit
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, Paris, France. Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668 Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Rupérez
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668 Madrid, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Barbas
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. Department of Cardiology, Instituto de Investigación Sanitaria (IIS), Fundación Jiménez Díaz Hospital, Madrid, Spain. thomas.langer@uni-koeln.de bibanez@cnic.es.
authors.forename: Borja
authors.initials: B
authors.lastname: Ibañez
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Max-Planck-Institute for Biology of Aging, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany. thomas.langer@uni-koeln.de bibanez@cnic.es.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D047108:Embryonic Development; D005260:Female; D020558:GTP Phosphohydrolases; D017353:Gene Deletion; D006321:Heart / Q000196:embryology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D063306:Mitophagy; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D059748:Proteolysis
chemical_list: D020558:GTP Phosphohydrolases; D008666:Metalloendopeptidases; D045726:Metalloproteases; D024101:Mitochondrial Proteins; C572960:OMA1 protein, mouse; C000588588:Yme1l1 protein, mouse; C498809:Opa1 protein, mouse