Raiff Anat, Zhao Shidong, Bekturova Aizat, Zenge Colin, Mazor Shir, Chen Xinyan, Ru Wenwen, Makaros Yaara, Ast Tslil, Ordureau Alban, Xu Chao, Koren Itay
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
MOE Key Laboratory for Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Nat Chem Biol. 2025 Apr 22. doi: 10.1038/s41589-025-01894-4.
Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.
线粒体稳态通过复杂的调控机制得以维持，包括涉及融合和裂变过程的线粒体动力学平衡。该调控中的一个核心参与者是泛素-蛋白酶体系统（UPS），它控制着关键线粒体蛋白的降解。在本研究中，我们确定了Cullin-RING E3连接酶2（CRL2）及其底物受体FEM1B是线粒体动力学的关键调节因子。通过蛋白质组学分析，我们在此证明FEM1B控制着PLD6的周转，PLD6是线粒体动力学的关键调节因子。利用结构和生化方法，我们表明FEM1B与PLD6发生物理相互作用，并且这种相互作用通过FEM1B与线粒体导入受体TOM20的直接结合而得以促进。FEM1B的缺失或FEM1B-TOM20相互作用的破坏会损害PLD6的降解并诱导线粒体缺陷，模拟PLD6过表达的表型。这些发现强调了FEM1B在维持线粒体形态中的重要性，并为UPS如何调节线粒体稳态提供了进一步的机制见解。
