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.

中文翻译：

---

生理性线粒体碎裂是心脏对能量需求增加的正常适应。

基本原理：线粒体在心脏中发挥双重作用，负责满足能量需求和调节细胞死亡。范式认为线粒体裂变和断裂是病理应激的结果，例如缺血，是线粒体健康状况不佳的指标，并导致线粒体自噬和细胞死亡。然而，最近的研究表明，抑制裂变也会导致线粒体功能下降和心脏损伤，这表明裂变对于维持心脏和线粒体生物能稳态很重要。

目的：本研究的目的是确定线粒体裂变和断裂是否可以成为心脏在正常生理应激（如运动）期间增强线粒体和心脏功能的一种适应性机制。

方法和结果：我们证明了心脏线粒体裂变作为对增加的能量需求的正常适应的新作用。在次极限运动期间，生理性线粒体断裂导致线粒体功能增强而非受损，并且部分由 β1-肾上腺素能受体信号传导介导。与病理性片段化类似，生理性片段化是由动力蛋白相关蛋白 1 的激活诱导的；然而，与病理性碎裂不同，膜电位得以维持，线粒体自噬的调节因子被下调。用 P110、Mdivi-1（线粒体分裂抑制剂）或在心脏特异性动力相关蛋白 1 消融的小鼠中抑制裂变可显着降低运动能力。

结论：这些发现证明了生理线粒体破碎以满足运动的能量需求，并为不断发展的概念框架提供额外支持，其中线粒体裂变和破碎在线粒体维持正常生理和反应之间的平衡中发挥作用到疾病。