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.

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.

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.

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 …