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

Shaofan Hu; Jing Feng; Meng Wang; Reziyamu Wufuer; Keli Liu; Zhengwen Zhang; Yiguo Zhang

doi:10.1016/j.redox.2022.102470

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

Redox Biol. 2022 Nov:57:102470. doi: 10.1016/j.redox.2022.102470. Epub 2022 Sep 13.

Authors

Shaofan Hu¹, Jing Feng¹, Meng Wang², Reziyamu Wufuer¹, Keli Liu¹, Zhengwen Zhang³, Yiguo Zhang⁴

Affiliations

¹ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering & Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China.
² Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering & Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China.
³ Laboratory of Neuroscience, Institute of Cognitive Neuroscience and School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, England, United Kingdom.
⁴ Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering & Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: yiguozhang@cqu.edu.cn.

Abstract

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.

Keywords: Antioxidant response; GABP(NRF2); Metabolism; Mitochondrion; Nrf1; Nrf2; ROS; Redox regulation; UCP2; UPR(mt); miR-195; miR-497; αPal(NRF1).