Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
EMBO J. 2020 Dec 15;39(24):e105074. doi: 10.15252/embj.2020105074. Epub 2020 Nov 17.
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.
线粒体的连接性受融合和分裂之间的平衡调节。许多人类疾病与线粒体连接过度有关，这是由于分裂的动力相关 GTP 酶 Drp1 受损所致。在这里，我们报告了一种线粒体应激反应，称为线粒体保护，它可以根据线粒体连接性的增加来调整融合和分裂的平衡。在缺乏 Drp1 的细胞中，线粒体发生过度融合。然而，过度融合并不能完全连接线粒体，因为另两种介导融合的动力相关 GTP 酶 Opa1 和 mitofusin 1 会被蛋白水解失活。药理学和遗传学实验表明，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，而不会影响 Drp1 敲除细胞的整体膜电位。在 Drp1 敲除细胞中重新激活 Opa1 和 Mitofusin 1 会进一步将线粒体连接起来，形成超融合，从而导致生物能量缺陷。这些发现揭示了一种意想不到的保护机制，可以防止线粒体的极度融合，从而在平衡向过度连接转移时维持线粒体的功能。
