Reactive oxygen species control protein degradation at the mitochondrial import gate

Rachael McMinimy; Andrew G Manford; Christine L Gee; Srividya Chandrasekhar; Gergey Alzaem Mousa; Joelle Chuang; Lilian Phu; Karen Y Shih; Christopher M Rose; John Kuriyan; Baris Bingol; Michael Rapé

doi:10.1016/j.molcel.2024.11.004

Reactive oxygen species control protein degradation at the mitochondrial import gate

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

Authors

Affiliations

¹ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
² Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
³ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA.
⁴ Helen Wills Neuroscience Institute, University of California at Berkeley, Berkeley, CA 94720, USA.
⁵ Genentech Inc. South San Francisco, South San Francisco, CA 94080, USA.
⁶ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].

PMID: 39642856
PMCID: PMC11649020 (available on 2025-12-05)
DOI: 10.1016/j.molcel.2024.11.004

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 (CUL2^FEM1B), 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 CUL2^FEM1B 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.

MeSH terms

Animals
Cullin Proteins / genetics
Cullin Proteins / metabolism
Electron Transport Complex III / genetics
Electron Transport Complex III / metabolism
Electron Transport Complex IV / genetics
Electron Transport Complex IV / metabolism
HEK293 Cells
Humans
Mitochondria* / metabolism
Mitochondrial Precursor Protein Import Complex Proteins / metabolism
Oxidative Stress
Proteolysis*
Reactive Oxygen Species* / metabolism

Substances

Reactive Oxygen Species
Electron Transport Complex III
Cullin Proteins
Electron Transport Complex IV
Mitochondrial Precursor Protein Import Complex Proteins