Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice

A change of heart (mitochondria) 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] INTRODUCTION Mitochondria are essential organelles whose form and function are inextricably linked. Balanced fusion and fission events shape mitochondria to meet metabolic demands and to ensure removal of damaged organelles. A fragmentation of the mitochondrial network occurs in response to cellular stress and is observed in a wide variety of disease conditions, including heart failure, neurodegenerative disorders, cancer, and obesity. However, the physiological relevance of stress-induced mitochondrial fragmentation remains unclear. RATIONALE Proteolytic processing of the dynamin-like guanosine triphosphatase (GTPase) OPA1 in the inner membrane of mitochondria is emerging as a critical regulatory step to balance mitochondrial fusion and fission. Two mitochondrial proteases, OMA1 and the AAA protease YME1L, cleave OPA1 from long (L-OPA1) to short (S-OPA1) forms. L-OPA1 is required for mitochondrial fusion, but S-OPA1 is not, although accumulation of S-OPA1 in excess accelerates fission. In cultured mammalian cells, stress conditions activate OMA1, which cleaves L-OPA1 and inhibits mitochondrial fusion resulting in mitochondrial fragmentation. In this study, we generated conditional mouse models for both YME1L and OMA1 and examined the role of OPA1 processing and mitochondrial fragmentation in the heart, a metabolically demanding organ that depends critically on mitochondrial functions. RESULTS Deletion of Yme1l in cardiomyocytes did not grossly affect mitochondrial respiration but induced the proteolytic cleavage of OPA1 by the stress-activated peptidase OMA1 and drove fragmentation of mitochondria in vivo. These mice suffered from dilated cardiomyopathy characterized by well-established features of heart failure that include necrotic cell death, fibrosis and ventricular remodelling, and a metabolic switch away from fatty acid oxidation and toward glucose use. We discovered that additional deletion of Oma1 in cardiomyocytes prevented OPA1 processing altogether and restored normal mitochondrial morphology and cardiac health. On the other hand, mice lacking YME1L in both skeletal muscle and cardiomyocytes exhibited normal cardiac function and life span despite mitochondrial fragmentation in cardiomyocytes. Imbalanced OPA1 processing in skeletal muscle, which is an insulin signaling tissue, induced systemic glucose intolerance and prevented cardiac glucose overload and cardiomyopathy. We observed a similar effect on cardiac metabolism upon feeding mice lacking Yme1l in cardiomyocytes a high-fat diet, which preserved heart function despite mitochondrial fragmentation. CONCLUSION Our work highlights the importance of balanced fusion and fission of mitochondria for cardiac function and unravels an intriguing link between mitochondrial dynamics and cardiac metabolism in the adult heart in vivo. Mitochondrial fusion mediated by L-OPA1 preserves cardiac function, whereas its stress-induced processing by OMA1 and mitochondrial fragmentation triggers dilated cardiomyopathy and heart failure. In contrast to previous genetic models of the mitochondrial fusion machinery, mice lacking Yme1l in cardiomyocytes do not show pleiotropic respiratory deficiencies and thus provide a tool to directly assess the physiological importance of mitochondrial dynamics. Preventing mitochondrial fragmentation by deleting Oma1 protects against cell death and heart failure. The identification of OMA1 as a critical regulator of mitochondrial morphology and cardiomyocyte survival holds promise for translational applications in cardiovascular medicine. Mitochondrial fragmentation induces a metabolic switch from fatty acid to glucose utilization in the heart. It turns out that reversing this switch and restoring normal cardiac metabolism is sufficient to preserve heart function despite mitochondrial fragmentation. These findings raise the intriguing possibility that the switch in fuel usage that occurs in the failing adult heart may, in fact, be maladaptive and could contribute to the pathogenesis of heart failure. Critical role of balanced mitochondrial fusion and fission for cardiac metabolism and heart function. Induced processing of the dynamin-like GTPase OPA1 in the inner membrane by the stress-activated peptidase OMA1 leads to mitochondrial fragmentation, cardiomyopathy, and heart failure, which is characterized by a switch in fuel utilization. Heart function can be preserved by reversing this metabolic switch without suppressing mitochondrial fragmentation. 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.