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

doi:10.1038/s41598-018-23884-4

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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29 Scopus citations

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 language	English
Article number	7420
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-23884-4
State	Published - 1 Dec 2018
Externally published	Yes

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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), Article 7420. https://doi.org/10.1038/s41598-018-23884-4

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title = "Mitochondrial complex I activity signals antioxidant response through ERK5",

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.",

author = "Khan, {Abrar Ul Haq} and Nerea Allende-Vega and Delphine Gitenay and Johan Garaude and Vo, {Dang Nghiem} and Sana Belkhala and Sabine Gerbal-Chaloin and Claire Gondeau and Martine Daujat-Chavanieu and C{\'e}cile Delettre and Stefania Orecchioni and Giovanna Talarico and Francesco Bertolini and Alberto Anel and Cuezva, {Jos{\'e} M.} and Enriquez, {Jose A.} and Guillaume Cartron and Lecellier, {Charles Henri} and Javier Hernandez and Martin Villalba",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41598-018-23884-4",

language = "English",

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Khan, AUH, Allende-Vega, N, Gitenay, D, Garaude, J, Vo, DN, Belkhala, S, Gerbal-Chaloin, S, Gondeau, C, Daujat-Chavanieu, M, Delettre, C, Orecchioni, S, Talarico, G, Bertolini, F, Anel, A, Cuezva, JM, Enriquez, JA, Cartron, G, Lecellier, CH, Hernandez, J & Villalba, M 2018, 'Mitochondrial complex I activity signals antioxidant response through ERK5', Scientific Reports, vol. 8, no. 1, 7420. https://doi.org/10.1038/s41598-018-23884-4

TY - JOUR

T1 - Mitochondrial complex I activity signals antioxidant response through ERK5

AU - Khan, Abrar Ul Haq

AU - Allende-Vega, Nerea

AU - Gitenay, Delphine

AU - Garaude, Johan

AU - Vo, Dang Nghiem

AU - Belkhala, Sana

AU - Gerbal-Chaloin, Sabine

AU - Gondeau, Claire

AU - Daujat-Chavanieu, Martine

AU - Delettre, Cécile

AU - Orecchioni, Stefania

AU - Talarico, Giovanna

AU - Bertolini, Francesco

AU - Anel, Alberto

AU - Cuezva, José M.

AU - Enriquez, Jose A.

AU - Cartron, Guillaume

AU - Lecellier, Charles Henri

AU - Hernandez, Javier

AU - Villalba, Martin

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41598-018-23884-4

DO - 10.1038/s41598-018-23884-4

M3 - Article

C2 - 29743487

AN - SCOPUS:85046903394

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 7420

ER -

Mitochondrial complex I activity signals antioxidant response through ERK5

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