Physiological 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 fssion 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 fssion also results in decreased mitochondrial function and cardiac impairment, suggesting that fssion is important for maintaining cardiac and mitochondrial bioenergetic homeostasis. Objective: The purpose of this study is to determine whether mitochondrial fssion 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 fssion 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 ß1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynaminrelated protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fssion with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specifc dynamin-related protein 1 ablation signifcantly decreases exercise capacity. Conclusions: These fndings 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 fssion and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.