Nature. 2025 Mar 26.
Junbing Zhang,
Md Yousuf Ali,
Harrison Byron Chong,
Pei-Chieh Tien,
James Woods,
Carolina Noble,
Tristan Vornbäumen,
Zehra Ordulu,
Anthony P Possemato,
Stefan Harry,
Jay Miguel Fonticella,
Lina Fellah,
Drew Harrison,
Maolin Ge,
Neha Khandelwal,
Yingfei Huang,
Maëva Chauvin,
Anica Tamara Bischof,
Grace Marie Hambelton,
Magdy Farag Gohar,
Siwen Zhang,
MinGyu Choi,
Sara Bouberhan,
Esther Oliva,
Mari Mino-Kenudson,
Natalya N Pavlova,
Michael Lawrence,
Justin F Gainor,
Sean A Beausoleil,
Nabeel Bardeesy,
Raul Mostoslavsky,
David Pépin,
Christopher J Ott,
Brian Liau,
Liron Bar-Peled.
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.