Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks

Abstract

There is hitherto no literature available for explaining two distinct, but confused, Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated α-Pal). Thus, we have here identified that Nfe2l1Nrf1 and α-PalNRF1 exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1-/- leads to substantial decreases in expression levels of α-PalNRF1 and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2-/- MEFs but with an exception that both GSTa1 and Aldh1a1 were distinguishably upregulated in Nfe2l1-/- MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of α-PalNRF1 and TFAM were validated in Keap1-/- MEFs. However, human α-PalNRF1 expression was unaltered by hNfe2l1α-/-, hNfe2l2-/-ΔTA, or even hNfe2l1α-/-+siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occurred in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2, and cotarget genes were downexpressed in α-PalNRF1+/- MEFs. On the contrary, upregulation of human Nfe2l1, Nfe2l2, and relevant reporter genes took place after silencing of α-PalNRF1, but their downregulation occurred upon ectopic expression of α-PalNRF1. Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides α-PalNRF1. Overall, these across-talks amongst Nfe2l1, Nfe2l2, and α-PalNRF1, along with Pitx2, are integrated from the endoplasmic reticulum towards the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the robust balance of distinct cellular oxidative respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. In addition, it is of crucial importance to note that, in view of such mutual interregulation of these transcription factors, it should be severely taken much cautions to interpret those relevant experimental results obtained from knockout of Nfe2l1, Nfe2l2, α-Pal or Pitx2, or their gain-of-functional mutants.

NRF1 Alleviated Oxidative Stress of Glioblastoma Cells by Regulating NOR1

“…In our study, we found that H 2 O 2 -induced oxidative stress inhibited proliferation, migration and invasion of U251 cells and promoted cell apoptosis, which was consistent with the results of Dalavaikodihalli et al (2019). NRF1, a redox-sensitive transcription factor, is vital for maintaining healthy redox homeostasis (Yuan et al, 2018;Zhang et al, 2020). Deletion of NRF1 function leads to a sharp increase in ROS and oxidative damage (Hu et al, 2022).…”

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

“…To gain an insight into the underlying mechanism for mitochondrial dysfunction caused by loss of Nrf1α –∕– , we here examined the constitutive expression of two nuclear respiratory factors αPal NRF1 and GABPα NRF2 [ 38 , 39 ], cofactor PGC1α, and critical target genes (responsible for mitochondrial DNA replication and transcription, ETC/OXPHOS gene expression, and mitochondrial biogenesis [ 40 ]). The results showed that basal mRNA expression levels of αPal NRF1 , GABPα NRF2 and co-targeting mitochondrial transcription factors TFAM (transcription factor A, mitochondrial), TFB1M (transcription factor B1, mitochondrial) and TFB2M (transcription factor B2, mitochondrial), together with PGC1α , but not PGC1ß , were down-regulated, though to different extents, in Nrf1α –∕– cells ( Fig.…”

Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species (ROS) in human hepatoma cells, which is alleviated by 2-bromopalmitate

“…No reuse allowed without permission. (14,23), protein homeostasis (proteostasis) (12,24), redox balance and signaling control (25,26). It is of crucial significance to note that the experimental cell model of Nrf1α -/with pathophysiological phenotypes appears to largely resemble those manifested by the liver-specific Nrf1 knockout mice.…”