Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile X syndrome. FMRP dysfunction disrupts mitochondrial health in neurons, but it is unclear how FMRP supports mitochondrial homoeostasis. Here we demonstrate that FMRP granules are recruited to the mitochondrial midzone, where they mark mitochondrial fission sites in axons and dendrites. Endolysosomal vesicles contribute to FMRP granule positioning around mitochondria and facilitate FMRP-associated fission via Rab7 GTP hydrolysis. Cryo-electron tomography and real-time translation imaging reveal that mitochondria-associated FMRP granules are ribosome-rich structures that serve as sites of local protein synthesis. Specifically, FMRP promotes local translation of mitochondrial fission factor (MFF), selectively enabling replicative fission at the mitochondrial midzone. Disrupting FMRP function dysregulates mitochondria-associated MFF translation and perturbs fission dynamics, resulting in increased peripheral fission and an irregular distribution of mitochondrial nucleoids. Thus, FMRP regulates local translation of MFF in neurons, enabling precise control of mitochondrial fission.

脆性 X 信使核糖核蛋白 （FMRP） 是翻译的关键调节因子，其功能障碍会导致脆性 X 综合征。FMRP 功能障碍会破坏神经元中的线粒体健康，但目前尚不清楚 FMRP 如何支持线粒体匀态。在这里，我们证明 FMRP 颗粒被募集到线粒体中区，在那里它们标记轴突和树突中的线粒体裂变位点。内溶酶体囊泡有助于 FMRP 颗粒在线粒体周围定位，并通过 Rab7 GTP 水解促进 FMRP 相关裂变。冷冻电子断层扫描和实时翻译成像显示，线粒体相关的 FMRP 颗粒是富含核糖体的结构，可作为局部蛋白质合成的位点。具体来说，FMRP 促进线粒体裂变因子 （MFF） 的局部翻译，选择性地在线粒体中区实现复制裂变。破坏 FMRP 功能会失调线粒体相关的 MFF 翻译并扰乱裂变动力学，导致外周裂变增加和线粒体类核分布不规则。因此，FMRP 调节神经元中 MFF 的局部翻译，从而能够精确控制线粒体裂变。