Mitochondrial complex I activity signals antioxidant response through ERK5

Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Johan Garaude, Dang Nghiem Vo, Sana Belkhala, Sabine Gerbal-Chaloin, Claire Gondeau, Martine Daujat-Chavanieu, Cécile Delettre, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Alberto Anel, José M. Cuezva, Jose A. Enriquez, Guillaume Cartron, Charles Henri Lecellier, Javier Hernandez, Martin Villalba

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Abstract

Oxidative phosphorylation (OXPHOS) generates ROS as a byproduct of mitochondrial complex I activity. ROS-detoxifying enzymes are made available through the activation of their antioxidant response elements (ARE) in their gene promoters. NRF2 binds to AREs and induces this anti-oxidant response. We show that cells from multiple origins performing OXPHOS induced NRF2 expression and its transcriptional activity. The NRF2 promoter contains MEF2 binding sites and the MAPK ERK5 induced MEF2-dependent NRF2 expression. Blocking OXPHOS in a mouse model decreased Erk5 and Nrf2 expression. Furthermore, fibroblasts derived from patients with mitochondrial disorders also showed low expression of ERK5 and NRF2 mRNAs. Notably, in cells lacking functional mitochondrial complex I activity OXPHOS did not induce ERK5 expression and failed to generate this anti-oxidant response. Complex I activity induces ERK5 expression through fumarate accumulation. Eukaryotic cells have evolved a genetic program to prevent oxidative stress directly linked to OXPHOS and not requiring ROS.

Original languageEnglish
Article number7420
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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    Khan, A. U. H., Allende-Vega, N., Gitenay, D., Garaude, J., Vo, D. N., Belkhala, S., Gerbal-Chaloin, S., Gondeau, C., Daujat-Chavanieu, M., Delettre, C., Orecchioni, S., Talarico, G., Bertolini, F., Anel, A., Cuezva, J. M., Enriquez, J. A., Cartron, G., Lecellier, C. H., Hernandez, J., & Villalba, M. (2018). Mitochondrial complex I activity signals antioxidant response through ERK5. Scientific Reports, 8(1), [7420]. https://doi.org/10.1038/s41598-018-23884-4