Journal Article

Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice

Wai, Timothy, Benit, Paule, Merkwirth, Carsten, Baker, Michael J., Rupérez, Francisco Javier, García-Prieto, Jaime, Ibañez, Borja, Langer, Thomas, Rustin, Pierre, Barbas, Coral

2015

Overview

Mitochondria provide an essential source of energy to drive cellular processes and are particularly important in heart muscle cells (see the Perspective by Gottlieb and Bernstein). After birth, the availability of oxygen and nutrients to organs and tissues changes. This invokes changes in metabolism. Gong et al. studied the developmental transitions in mouse heart mitochondria soon after birth. Mitochondria were replaced wholesale via mitophagy in cardiomyocytes over the first 3 weeks after birth. Preventing this turnover by interfering with parkin-mediated mitophagy specifically in cardiomyocytes prevented the normal metabolic transition and caused heart failure. Thus, the heart has coopted a quality-control pathway to facilitate a major developmental transition after birth. Wai et al. examined the role of mitochondrial fission and fusion in mouse cardiomyocytes. Disruption of these processes led to “middle-aged” death from a form of dilated cardiomyopathy. Mice destined to develop cardiomyopathy were protected by feeding with a high-fat diet, which altered cardiac metabolism. Science , this issue p. 10.1126/science.aad2459 , p. 10.1126/science.aad0116 ; see also p. 1162 Mitochondrial fragmentation in cardiomyocytes causes heart failure in mice and can be rescued by metabolic intervention. [Also see Perspective by Gottlieb and Bernstein ] 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.

• Publisher: The American Association for the Advancement of Science,American Association for the Advancement of Science (AAAS)
• Subject: Ablation / Adults / Animals / Birth / Cardiomyopathy, Dilated - genetics / Cardiomyopathy, Dilated - metabolism / Cardiomyopathy, Dilated - pathology / Diet / Diet, High-Fat / Embryonic Development / Failure / Fatty acids / Female / Fragmentation / Gene Deletion / GTP Phosphohydrolases / Heart / Heart - embryology / Heart failure / Heart Failure - genetics / Heart Failure - metabolism / Heart Failure - pathology / Life Sciences / Male / Metabolism / Metalloendopeptidases - genetics / Metalloproteases - genetics / Metalloproteases - metabolism / Mice / Mice, Knockout / Mitochondria / Mitochondria, Heart - metabolism / Mitochondria, Heart - ultrastructure / Mitochondrial Degradation / Mitochondrial Dynamics / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Morphology / Mortality / Muscle, Skeletal - enzymology / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - enzymology / Myocytes, Cardiac - pathology / Obesity / Physiology / Proteolysis / Rodents