Mitochondrial Complex I activity signals antioxidant response through ERK5

作者：Khan Abrar Ul Haq; Allende Vega Nerea; Gitenay Delphine; Garaude Johan; Dang NghiemVo; Belkhala Sana; Gerbal Chaloin Sabine; Gondeau Claire; Daujat Chavanieu Martine; Delettre Cecile; Orecchioni Stefania; Talarico Giovanna; Bertolini Francesco; Anel Alberto; Cuezva Jose M; Enriquez Jose A; Cartron Guillaume; Lecellier Charles Henri; Hernandez Javier; Villalba Martin

来源：Scientific Reports, 2018, 8(1): 7420.

DOI：10.1038/s41598-018-23884-4

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>NRF2</jats:italic> promoter contains MEF2 binding sites and the MAPK ERK5 induced MEF2-dependent NRF2 expression. Blocking OXPHOS in a mouse model decreased <jats:italic>Erk5</jats:italic> and <jats:italic>Nrf2</jats:italic> expression. Furthermore, fibroblasts derived from patients with mitochondrial disorders also showed low expression of <jats:italic>ERK5</jats:italic> and <jats:italic>NRF2</jats:italic> 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.</jats:p>

• 出版日期2018-5-9