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. 2024 Dec 5;84(23):4612-4628.e13.
doi: 10.1016/j.molcel.2024.11.004.

Reactive oxygen species control protein degradation at the mitochondrial import gate

Rachael McMinimy  1 , Andrew G Manford  2 , Christine L Gee  3 , Srividya Chandrasekhar  1 , Gergey Alzaem Mousa  4 , Joelle Chuang  1 , Lilian Phu  5 , Karen Y Shih  1 , Christopher M Rose  5 , John Kuriyan  2 , Baris Bingol  5 , Michael Rapé  6
Affiliations

Reactive oxygen species control protein degradation at the mitochondrial import gate

Rachael McMinimy et al. Mol Cell. .

Abstract

While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.

Keywords: FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin.

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Conflict of interest statement

Declaration of interests M.R. is a cofounder and SAB member of Nurix, Zenith, and Lyterian Therapeutics; SAB member for Vicinitas Therapeutics; and iPartner at The Column Group. J.K. is cofounder and SAB member of Nurix. L.P., C.R., and B.B. are employees of Genentech.

References

    1. Kauppila TES, Kauppila JHK, and Larsson NG (2017). Mammalian Mitochondria and Aging: An Update. Cell Metab 25, 57–71. 10.1016/j.cmet.2016.09.017. - DOI - PubMed
    1. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, and Schumacker PT (1998). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A 95, 11715–11720. 10.1073/pnas.95.20.11715. - DOI - PMC - PubMed
    1. Sies H, Berndt C, and Jones DP (2017). Oxidative Stress. Annu Rev Biochem. 10.1146/annurev-biochem-061516-045037. - DOI - PubMed
    1. Forman HJ, and Zhang H (2021). Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 20, 689–709. 10.1038/s41573-021-00233-1. - DOI - PMC - PubMed
    1. Cao J, Schulte J, Knight A, Leslie NR, Zagozdzon A, Bronson R, Manevich Y, Beeson C, and Neumann CA (2009). Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity. EMBO J 28, 1505–1517. 10.1038/emboj.2009.101. - DOI - PMC - PubMed

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