Author
Listed:
- Junbing Zhang
(Massachusetts General Hospital Cancer Center
Chinese Academy of Sciences)
- Md Yousuf Ali
(Massachusetts General Hospital Cancer Center)
- Harrison Byron Chong
(Massachusetts General Hospital Cancer Center)
- Pei-Chieh Tien
(Massachusetts General Hospital Cancer Center)
- James Woods
(Harvard University)
- Carolina Noble
(Massachusetts General Hospital Cancer Center)
- Tristan Vornbäumen
(Massachusetts General Hospital Cancer Center)
- Zehra Ordulu
(Department of Pathology)
- Anthony P. Possemato
(Cell Signaling Technology)
- Stefan Harry
(Massachusetts General Hospital Cancer Center)
- Jay Miguel Fonticella
(Massachusetts General Hospital Cancer Center)
- Lina Fellah
(Massachusetts General Hospital Cancer Center)
- Drew Harrison
(Massachusetts General Hospital Cancer Center)
- Maolin Ge
(Massachusetts General Hospital Cancer Center)
- Neha Khandelwal
(Massachusetts General Hospital Cancer Center)
- Yingfei Huang
(Massachusetts General Hospital Cancer Center)
- Maëva Chauvin
(Massachusetts General Hospital)
- Anica Tamara Bischof
(Massachusetts General Hospital Cancer Center)
- Grace Marie Hambelton
(Massachusetts General Hospital)
- Magdy Farag Gohar
(Massachusetts General Hospital Cancer Center)
- Siwen Zhang
(Massachusetts General Hospital Cancer Center)
- MinGyu Choi
(Massachusetts Institute of Technology)
- Sara Bouberhan
(Massachusetts General Hospital
Massachusetts General Hospital
Harvard Medical School)
- Esther Oliva
(Massachusetts General Hospital)
- Mari Mino-Kenudson
(Massachusetts General Hospital)
- Natalya N. Pavlova
(University of Utah)
- Michael Lawrence
(Massachusetts General Hospital Cancer Center
Harvard Medical School
Broad Institute of MIT and Harvard)
- Justin F. Gainor
(Massachusetts General Hospital
Harvard Medical School)
- Sean A. Beausoleil
(Cell Signaling Technology)
- Nabeel Bardeesy
(Massachusetts General Hospital Cancer Center
Massachusetts General Hospital
Harvard Medical School)
- Raul Mostoslavsky
(Massachusetts General Hospital
Harvard Medical School)
- David Pépin
(Massachusetts General Hospital)
- Christopher J. Ott
(Massachusetts General Hospital Cancer Center
Massachusetts General Hospital
Harvard Medical School)
- Brian Liau
(Harvard University)
- Liron Bar-Peled
(Massachusetts General Hospital Cancer Center
Massachusetts General Hospital
Harvard Medical School)
Abstract
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.
Suggested Citation
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 &, 2025.
"Oxidation of retromer complex controls mitochondrial translation,"
Nature, Nature, vol. 641(8064), pages 1048-1058, May.
Handle:
RePEc:nat:nature:v:641:y:2025:i:8064:d:10.1038_s41586-025-08756-y
DOI: 10.1038/s41586-025-08756-y
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