浙江大学医学院张强研究小组近日取得一项新成果。经过不懈努力，他们的最新研究探明了线粒体裂变因子感知并控制铁下垂。该研究于2026年9月16日发表于国际一流学术期刊《自然》杂志上。

铁死亡是一种由铁依赖性脂质过氧化驱动的调节性细胞死亡形式，与多种病理状态相关。尽管线粒体和其他细胞器日益被认为是铁死亡的重要调节因子，但将细胞器动力学与铁死亡执行耦合起来的统一机制仍难以捉摸。在此，研究人员利用定量磷酸蛋白质组学，鉴定出线粒体分裂因子（MFF）是铁死亡选择性关键调控因子。机制上，脂质介质17-HETE促进MFF在Ser155位点的磷酸化，从而触发线粒体和过氧化物酶体的协同片段化和功能障碍。这种重塑加剧了细胞器间串扰，放大了氧化应激，并加速了铁死亡。为了监测活细胞中的这一磷酸化事件，研究人员开发了MFF–SPARK，一种基于相分离的生物传感器，用于通过MFF激活实时追踪铁死亡。利用MFF–SPARK，研究人员鉴定出PKCβ和DUSP22是一对协调的激酶-磷酸酶，调控MFF磷酸化。他们还发现阿维菌素B1作为PKCβ–MFF轴的药理学激活剂，可在体内使肿瘤对铁死亡敏感。总之，研究人员的发现确立了MFF磷酸化是铁死亡相关细胞器重塑的中心调控节点，并为监测和药理学探究铁死亡提供了概念框架和工具箱。

附：英文原文

Title: Mitochondrial fission factor senses and governs ferroptosis

Author: Dai, Songjun, Dai, Xiaoyan, Zhang, Tingting, Qi, Yuanyuan, Yang, Xinquan, Diao, Pengfei, Ge, Chaodong, Huang, Wenxiang, Ran, Jisheng, Yang, Xueliang, Zhang, Peng, Zheng, Keke, Wang, Ruijun, Qian, Hong, Zhang, Kunxiao, Wu, Junbing, Fu, Caiyun, Ba, Qian, Min, Junxia, Wang, Fudi, Zhang, Qiang

Issue&Volume: 2026-09-16

Abstract: Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation and is implicated in diverse pathological states1,2,3,4. Although mitochondria and other organelles are increasingly being recognized as important modulators of ferroptosis5,6,7, a unifying mechanism that couples organelle dynamics to ferroptotic execution has remained elusive. Here using quantitative phosphoproteomics, we identified mitochondrial fission factor (MFF) as a key ferroptosis-selective regulator. Mechanistically, the lipid mediator 17-HETE promotes phosphorylation of MFF at Ser155, which triggers the coordinated fragmentation and dysfunction of mitochondria and peroxisomes. This remodelling intensifies interorganelle crosstalk, amplifies oxidative stress and accelerates ferroptotic death. To monitor this phosphorylation event in living cells, we developed MFF–SPARK, a phase-separation-based biosensor, for real-time tracking of ferroptosis through MFF activation. Using MFF–SPARK, we identified PKCβ and DUSP22 as a coordinated kinase–phosphatase pair that governs MFF phosphorylation. We also discovered avermectin B1 as a pharmacological activator of the PKCβ–MFF axis, which can sensitize tumours to ferroptosis in vivo. Together, our findings establish MFF phosphorylation as a central regulatory node in ferroptosis-associated organelle remodelling and provide a conceptual framework and toolbox for monitoring and pharmacologically interrogating ferroptosis.

DOI: 10.1038/s41586-026-11020-6

Source: https://www.nature.com/articles/s41586-026-11020-6