The connectivity of mitochondria is regulated by a balance between fusion and division. Many human diseases are associated with excessive mitochondrial connectivity due to impaired Drp1, a dynamin‐related GTPase that mediates division. Here, we report a mitochondrial stress response, named mitochondrial safeguard, that adjusts the balance of fusion and division in response to increased mitochondrial connectivity. In cells lacking Drp1, mitochondria undergo hyperfusion. However, hyperfusion does not completely connect mitochondria because Opa1 and mitofusin 1, two other dynamin‐related GTPases that mediate fusion, become proteolytically inactivated. Pharmacological and genetic experiments show that the activity of Oma1, a metalloprotease that cleaves Opa1, is regulated by short pulses of the membrane depolarization without affecting the overall membrane potential in Drp1‐knockout cells. Re‐activation of Opa1 and Mitofusin 1 in Drp1‐knockout cells further connects mitochondria beyond hyperfusion, termed extreme fusion, leading to bioenergetic deficits. These findings reveal an unforeseen safeguard mechanism that prevents extreme fusion of mitochondria, thereby maintaining mitochondrial function when the balance is shifted to excessive connectivity.

中文翻译：

---

线粒体保护：一种应激反应，通过闪烁诱导的 Oma1 激活抵消极端融合并保护呼吸功能

线粒体的连通性受融合和分裂之间的平衡调节。由于 Drp1 受损，许多人类疾病与线粒体过度连接有关，Drp1 是一种介导分裂的与动力相关的 GTP 酶。在这里，我们报告了一种称为线粒体保护的线粒体应激反应，它调整融合和分裂的平衡以响应增加的线粒体连接性。在缺乏 Drp1 的细胞中，线粒体发生过度融合。然而，超融合并没有完全连接线粒体，因为 Opa1 和 mitofusin 1，另外两种介导融合的与动力相关的 GTP 酶，在蛋白水解上失活。药理和遗传实验表明 Oma1 的活性，一种切割 Opa1 的金属蛋白酶，受膜去极化的短脉冲调节，而不影响 Drp1 敲除细胞中的整体膜电位。Drp1 敲除细胞中 Opa1 和 Mitofusin 1 的重新激活进一步将线粒体连接到过度融合之外，称为极端融合，导致生物能量不足。这些发现揭示了一种不可预见的保护机制，可防止线粒体极端融合，从而在平衡转向过度连接时维持线粒体功能。