Oxidation of retromer complex controls mitochondrial translation

Junbing Zhang^#^{1

2}, Md Yousuf Ali^#³, Harrison Byron Chong^#³, Pei-Chieh Tien³, James Woods⁴, Carolina Noble³, Tristan Vornbäumen³, Zehra Ordulu⁵, Anthony P Possemato⁶, Stefan Harry³, Jay Miguel Fonticella³, Lina Fellah³, Drew Harrison³, Maolin Ge³, Neha Khandelwal³, Yingfei Huang³, Maëva Chauvin⁷, Anica Tamara Bischof³, Grace Marie Hambelton⁸, Magdy Farag Gohar³, Siwen Zhang³, MinGyu Choi⁹, Sara Bouberhan^{8

10

11}, Esther Oliva¹², Mari Mino-Kenudson¹², Natalya N Pavlova¹³, Michael Lawrence^{3

11

14}, Justin F Gainor^{8

11}, Sean A Beausoleil⁶, Nabeel Bardeesy^{3

8

11}, Raul Mostoslavsky^{8

11}, David Pépin⁷, Christopher J Ott^{3

8

11}, Brian Liau⁴, Liron Bar-Peled^{15

16

17}

Affiliations

¹ Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. junbingzhang@sinh.ac.cn.
² CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. junbingzhang@sinh.ac.cn.
³ Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁵ Brigham and Women's Hospital, Department of Pathology, Harvard Medical School, MA, USA.
⁶ Cell Signaling Technology, Danvers, MA, USA.
⁷ Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. lbar-peled@mgh.harvard.edu.
¹⁶ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
¹⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA. lbar-peled@mgh.harvard.edu.

^# Contributed equally.

PMID: 40140582
DOI: 10.1038/s41586-025-08756-y

Oxidation of retromer complex controls mitochondrial translation

Junbing Zhang et al. Nature. 2025 May.

. 2025 May;641(8064):1048-1058.

doi: 10.1038/s41586-025-08756-y. Epub 2025 Mar 26.

Authors

Affiliations

¹ Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. junbingzhang@sinh.ac.cn.
² CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. junbingzhang@sinh.ac.cn.
³ Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁵ Brigham and Women's Hospital, Department of Pathology, Harvard Medical School, MA, USA.
⁶ Cell Signaling Technology, Danvers, MA, USA.
⁷ Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. lbar-peled@mgh.harvard.edu.
¹⁶ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
¹⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA. lbar-peled@mgh.harvard.edu.

^# Contributed equally.

PMID: 40140582
DOI: 10.1038/s41586-025-08756-y

Abstract

Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration^1,2. 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.

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Conflict of interest statement

Competing interests: L.B.-P. is a founder, consultant and holds privately held equity in Scorpion Therapeutics. A.P.P. and S.A.B. are employees of Cell Signaling Technology. B.L. is a founder, member of the scientific advisory board, and equity holder in Light Horse Therapeutics. M.M.-K. has served as a compensated consultant for AstraZeneca, Roche, BMS, Innate, Boehringer-Ingelheim, Sanofi, Daiichi-Sankyo and AbbVie and has received royalties from Elsevier. J.F.G. has served as a compensated consultant for Amgen, AstraZeneca, Mariana Therapeutics, Mirati Therapeutics, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Silverback Therapeutics, Sanofi, Blueprint Medicines, Bristol Myers Squibb, Genentech, Gilead Sciences, ITeos Therapeutics, Jounce Therapeutics, Karyopharm Therapeutics, Lilly/Loxo, Merck, Moderna Therapeutics and Takeda; has received honorarium from Novartis, Merck, Novartis, Pfizer, Takeda; has received institutional research funding from Adaptimmune, Alexo Therapeutics, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Jounce Therapeutics, Merck, Moderna Therapeutics, Novartis, NextPoint Therapeutics and Palleon Pharmaceuticals; has recreived research support from Novartis, Genentech and Takeda; has equity in AI Proteins; and has an immediate family member who has equity in and is employed by Ironwood Pharmaceuticals. All other authors declare no competing interests.

References

1. Chio, I. I. C. & Tuveson, D. A. ROS in cancer: the burning question. Trends Mol. Med. 23, 411–429 (2017). - PubMed - PMC - DOI
1. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010). - PubMed - PMC - DOI
1. Williams, E. T., Chen, X. & Moore, D. J. VPS35, the retromer complex and Parkinson’s disease. J. Parkinsons Dis. 7, 219–233 (2017). - PubMed - PMC - DOI
1. Liu, Y. & Birsoy, K. Metabolic sensing and control in mitochondria. Mol. Cell 83, 877–889 (2023). - PubMed - PMC - DOI
1. Bar-Peled, L. & Kory, N. Principles and functions of metabolic compartmentalization. Nat. Metab. 4, 1232–1244 (2022). - PubMed - PMC - DOI

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Oxidation of retromer complex controls mitochondrial translation

Affiliations

Oxidation of retromer complex controls mitochondrial translation

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Grants and funding

LinkOut - more resources

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Miscellaneous