Oxidation of retromer complex controls mitochondrial translation

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 and Liron Bar-Peled ()
Additional contact information
Junbing Zhang: Massachusetts General Hospital Cancer Center
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
Esther Oliva: Massachusetts General Hospital
Mari Mino-Kenudson: Massachusetts General Hospital
Natalya N. Pavlova: University of Utah
Michael Lawrence: Massachusetts General Hospital Cancer Center
Justin F. Gainor: Massachusetts General Hospital
Sean A. Beausoleil: Cell Signaling Technology
Nabeel Bardeesy: Massachusetts General Hospital Cancer Center
Raul Mostoslavsky: Massachusetts General Hospital
David Pépin: Massachusetts General Hospital
Christopher J. Ott: Massachusetts General Hospital Cancer Center
Brian Liau: Harvard University
Liron Bar-Peled: Massachusetts General Hospital Cancer Center

Nature, 2025, vol. 641, issue 8064, 1048-1058

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08756-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:641:y:2025:i:8064:d:10.1038_s41586-025-08756-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08756-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().