Publikationsdatum:
2016-01-20
Beschreibung:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wai, Timothy -- Garcia-Prieto, Jaime -- Baker, Michael J -- Merkwirth, Carsten -- Benit, Paule -- Rustin, Pierre -- Ruperez, Francisco Javier -- Barbas, Coral -- Ibanez, Borja -- Langer, Thomas -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):aad0116. doi: 10.1126/science.aad0116.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Max-Planck-Institute for Biology of Aging, Cologne, Germany. ; Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. ; Institute for Genetics, University of Cologne, 50674 Cologne, Germany. ; INSERM UMR 1141, Hopital Robert Debre, Paris, France. Universite Paris 7, Faculte de Medecine Denis Diderot, Paris, France. ; Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668 Madrid, Spain. ; Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. Department of Cardiology, Instituto de Investigacion Sanitaria (IIS), Fundacion Jimenez Diaz Hospital, Madrid, Spain. thomas.langer@uni-koeln.de bibanez@cnic.es. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785494" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Animals
;
Cardiomyopathy, Dilated/genetics/metabolism/pathology
;
Diet, High-Fat
;
Embryonic Development
;
Female
;
GTP Phosphohydrolases
;
Gene Deletion
;
Heart/embryology
;
Heart Failure/genetics/*metabolism/pathology
;
Male
;
Metalloendopeptidases/genetics
;
Metalloproteases/genetics/metabolism
;
Mice
;
Mice, Knockout
;
Mitochondria, Heart/*metabolism/ultrastructure
;
*Mitochondrial Degradation
;
*Mitochondrial Dynamics
;
Mitochondrial Proteins/genetics/metabolism
;
Muscle, Skeletal/enzymology
;
Myocardium/*metabolism/pathology
;
Myocytes, Cardiac/enzymology/pathology
;
Proteolysis
Print ISSN:
0036-8075
Digitale ISSN:
1095-9203
Thema:
Biologie
,
Chemie und Pharmazie
,
Informatik
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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