Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca²⁺ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.

中文翻译：

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Mfn2 在 ER 中的定位对其生物能功能和神经炎发育是必要的

Mfn2 是一种线粒体融合蛋白，具有与神经元和代谢紊乱的病理生理学有关的生物能功能。了解 Mfn2 的生物能机制可能有助于设计这些疾病的治疗方法。在这里，我们展示了使用内质网 (ER) 或线粒体靶向 Mfn2，Mfn2 对线粒体代谢的刺激需要其定位于 ER，这与其融合功能无关。位于 ER 的 Mfn2 与线粒体 Mfn1/2 相互作用，将 ER 和线粒体连接在一起，允许 Ca ²⁺从 ER 转移到线粒体以增强线粒体生物能学。这些发现的生理相关性在轴突生长过程中显示出来，此时 Mfn2 依赖性 ER-线粒体接触增加，这是正确神经元乔木生长所必需的。Mfn2 KO 神经元中减少的神经炎生长通过 ER 靶向 Mfn2 或人工 ER-线粒体系绳的表达恢复，表明 ER-线粒体接触的操作可用于治疗涉及 Mfn2 的病理状况。