Buntenbroich Ira, Anton Vincent, Perez-Hernandez Daniel, Simões Tânia, Gaedke Felix, Schauss Astrid, Dittmar Gunnar, Riemer Jan, Escobar-Henriques Mafalda
Institute for Genetics,University of Cologne, Cologne 50931, Germany.
Proteomics of Cellular Signaling, Luxembourg Institute of Health, Strassen 1445, Luxembourg.
iScience. 2023 Jun 7;26(7):107014. doi: 10.1016/j.isci.2023.107014. eCollection 2023 Jul 21.
Defects in mitochondrial fusion are at the base of many diseases. Mitofusins power membrane-remodeling events via self-interaction and GTP hydrolysis. However, how exactly mitofusins mediate fusion of the outer membrane is still unclear. Structural studies enable tailored design of mitofusin variants, providing valuable tools to dissect this stepwise process. Here, we found that the two cysteines conserved between yeast and mammals are required for mitochondrial fusion, revealing two novel steps of the fusion cycle. C381 is dominantly required for the formation of the -tethering complex, before GTP hydrolysis. C805 allows stabilizing the Fzo1 protein and the -tethering complex, just prior to membrane fusion. Moreover, proteasomal inhibition rescued Fzo1 C805S levels and membrane fusion, suggesting a possible application for clinically approved drugs. Together, our study provides insights into how assembly or stability defects in mitofusins might cause mitofusin-associated diseases and uncovers potential therapeutic intervention by proteasomal inhibition.
线粒体融合缺陷是许多疾病的根源。线粒体融合蛋白通过自身相互作用和GTP水解推动膜重塑事件。然而，线粒体融合蛋白究竟如何介导外膜融合仍不清楚。结构研究能够对线粒体融合蛋白变体进行定制设计，为剖析这一逐步过程提供了有价值的工具。在这里，我们发现酵母和哺乳动物之间保守的两个半胱氨酸是线粒体融合所必需的，揭示了融合循环的两个新步骤。在GTP水解之前，C381是形成拴系复合物所必需的主要因素。C805在膜融合之前允许稳定Fzo1蛋白和拴系复合物。此外，蛋白酶体抑制挽救了Fzo1 C805S的水平和膜融合，这表明临床批准的药物可能有应用价值。总之，我们的研究深入了解了线粒体融合蛋白的组装或稳定性缺陷可能如何导致与线粒体融合蛋白相关的疾病，并揭示了通过蛋白酶体抑制进行潜在治疗干预的方法。
