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.
Highlights
Oxidative phosphorylation (OXPHOS) generates reactive oxygen species (ROS) as a byproduct of mitochondrial complex I activity
Mitochondrial activity is directly linked to the most important antioxidant response in the absence of de novo increase in ROS levels. This implies that eukaryotic cells have evolved a genetic program to prevent oxidative stress directly linked to oxidative phosphorylation (OXPHOS) and not requiring ROS
We have previously described that leukemic cells performing OXPHOS generated an anti-oxidant response independently of ROS11
Summary
Oxidative phosphorylation (OXPHOS) generates ROS as a byproduct of mitochondrial complex I activity. The MAPK extracellular signal-regulated kinase-5 (ERK5), through the transcription factor MEF2, induces expression of miR-23 that inhibits KEAP-1 mRNA leading to NRF2 activation[11]. DCA induced mouse Erk[5], Nrf[2] and Nqo[1] mRNA in liver and spleen in a separate experiment in which C57BL/6 wild type mice were treated for different periods of time, 1 to 3 days, with DCA (Fig. 3B). Both cell lines increased NRF2 expression suggesting that ROS production was not essential for this induction (Fig. 4).
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