Physiologic Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand

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 pathologic 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 physiologic 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, "physiologic" mitochondrial fragmentation results in enhanced, rather than impaired mitochondrial function, and is mediated in-part by β1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 or in mice with cardiac specific Drp1 ablation, significantly 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.