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Sci Rep. 2018 May 9;8(1):7420. doi: 10.1038/s41598-018-23884-4.

Mitochondrial Complex I activity signals antioxidant response through ERK5.

Author information

1
IRMB, INSERM, Univ Montpellier, Montpellier, France.
2
Institut de Regenerative Medicine et Biothérapie (IRMB), CHU Montpellier, Montpellier, 34295, France.
3
Département d'Hépato-gastroentérologie A, Hôpital Saint Eloi, CHU Montpellier, France.
4
INSERM U1051, Institute of Neurosciences of Montpellier, Montpellier, France.
5
Department of Biology and Health Sciences, University of Montpellier, Montpellier, France.
6
Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
7
Department of Biochemistry and Molecular and Cellular Biology, Aragón Health Research Institute (IIS Aragón), University of Zaragoza, Zaragoza, Spain.
8
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, CIBERER, Universidad autónoma de Madrid, 28049, Madrid, Spain.
9
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Melchor Fernandez Almalgo, 3 28209, Madrid, Spain.
10
CIBERFES. Melchor Fernandez Almagro, 3 28209, Madrid, Spain.
11
Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, 80 avenue Augustin Fliche, 34295, Montpellier, France.
12
IGMM, CNRS, Univ. Montpellier, Montpellier, France.
13
Institut de Biologie Computationnelle, Montpellier, France.
14
IRMB, INSERM, Univ Montpellier, Montpellier, France. martin.villalba@inserm.fr.
15
Institut de Regenerative Medicine et Biothérapie (IRMB), CHU Montpellier, Montpellier, 34295, France. martin.villalba@inserm.fr.

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.

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