Oxidation of retromer complex controls mitochondrial translation

• 成果类型: Article
• 署名作者: Zhang, Junbing; Ali, Md Yousuf; Chong, Harrison Byron; Tien, Pei-Chieh; Woods, James; Noble, Carolina; Vornbaumen, Tristan; Ordulu, Zehra; Possemato, Anthony P.; Harry, Stefan; Fonticella, Jay Miguel; Fellah, Lina; Harrison, Drew; Ge, Maolin; Khandelwal, Neha; Huang, Yingfei; Chauvin, Maeva; Bischof, Anica Tamara; Hambelton, Grace Marie; Gohar, Magdy Farag; Zhang, Siwen; Choi, Mingyu; Bouberhan, Sara; Oliva, Esther; Mino-Kenudson, Mari; Pavlova, Natalya N.; Lawrence, Michael; Gainor, Justin F.; Beausoleil, Sean A.; Bardeesy, Nabeel; Mostoslavsky, Raul; Pepin, David; Ott, Christopher J.; Liau, Brian; Bar-Peled, Liron
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Chinese Academy of Sciences; Shanghai Institute of Nutrition & Health, CAS; University of Chinese Academy of Sciences, CAS; Harvard University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Cell Signaling Technology; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Utah System of Higher Education; University of Utah; Huntsman Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2932
• DOI: 10.1038/s41586-025-08756-y
• 发表日期: 2025-05-22
• 关键词: cancer; ros; proteins; vps35; base; identification

摘要

Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.