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Free keywords:
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
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.
