Michael Coronado1, Giovanni Fajardo1, Kim Nguyen1, Mingming Zhao1, Kristina Kooiker1, Gwanghyun Jung1, Dong-Qing Hu1, Sushma Reddy1, Erik Sandoval1, Aleksandr Stotland1, Roberta A Gottlieb1, Daniel Bernstein2. 1. From the Department of Pediatrics (Cardiology) (M.C., G.F., K.N., M.Z., K.K., G.J., D.-Q.H., S.R., E.S., D.B.) and Cardiovascular Research Institute (M.C., G.F., M.Z., K.K., G.J., D.-Q.H., S.R., E.S., D.B.), Stanford University, CA; and Molecular Cardiology Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (A.S., R.A.G.). 2. From the Department of Pediatrics (Cardiology) (M.C., G.F., K.N., M.Z., K.K., G.J., D.-Q.H., S.R., E.S., D.B.) and Cardiovascular Research Institute (M.C., G.F., M.Z., K.K., G.J., D.-Q.H., S.R., E.S., D.B.), Stanford University, CA; and Molecular Cardiology Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (A.S., R.A.G.). danb@stanford.edu.
Abstract
RATIONALE: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis. OBJECTIVE: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise. METHODS AND RESULTS: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity. CONCLUSIONS: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
RATIONALE: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis. OBJECTIVE: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise. METHODS AND RESULTS: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity. CONCLUSIONS: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
Authors: Bat-Erdene Myagmar; James M Flynn; Patrick M Cowley; Philip M Swigart; Megan D Montgomery; Kevin Thai; Divya Nair; Rumita Gupta; David X Deng; Chihiro Hosoda; Simon Melov; Anthony J Baker; Paul C Simpson Journal: Circ Res Date: 2017-02-20 Impact factor: 17.367
Authors: Massimo Bonora; Mariusz R Wieckowski; David A Sinclair; Guido Kroemer; Paolo Pinton; Lorenzo Galluzzi Journal: Nat Rev Cardiol Date: 2019-01 Impact factor: 32.419