Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical...

To defend against a vast variety of challenges in oxygenated environments, all life forms have evolutionally established a set of antioxidants, detoxification, and cytoprotective systems during natural selection and adaptive survival, to maintain cell redox homeostasis and organ integrity in the healthy development and growth. Such antioxidant defense systems are predominantly regulated by two key transcription factors Nrf1 and Nrf2, but the underlying mechanism(s) for their coordinated redox control remains elusive. Here, we found that loss of full-length Nrf1 led to a dramatic increase in reactive oxygen species (ROS) and oxidative damages in Nrf1α^-∕- cells, and this increase was not eliminated by drastic elevation of Nrf2, even though the antioxidant systems were also substantially enhanced by hyperactive Nrf2. Further studies revealed that the increased ROS production in Nrf1α^-∕- resulted from a striking impairment in the mitochondrial oxidative respiratory chain and its gene expression regulated by nuclear respiratory factors, called αPal^NRF1 and GABP^NRF2. In addition to the antioxidant capacity of cells, glycolysis was greatly augmented by aberrantly-elevated Nrf2, so to partially relieve the cellular energy demands, but aggravate its mitochondrial stress. The generation of ROS was also differentially regulated by Nrf1 and Nrf2 through miR-195 and/or mIR-497-mediated UCP2 pathway. Consequently, the epithelial-mesenchymal transformation (EMT) of Nrf1α^-∕- cells was activated by putative ROS-stimulated signaling via MAPK, HIF1α, NF-ƙB, PI3K and AKT, all players involved in cancer development and progression. Taken together, it is inferable that Nrf1 acts as a potent integrator of redox regulation by multi-hierarchical networks.