English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

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 Nfe2l1 Nrf1  and  α -Pal NRF1  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 -Pal NRF1  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 -Pal NRF1  and TFAM were validated in  Keap1 −/−   MEFs. However, human  α -Pal NRF1  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-Pal NRF1+/-   MEFs. On the contrary, upregulation of human Nfe2l1, Nfe2l2, and relevant reporter genes took place after silencing of  α -Pal NRF1 , but their downregulation occurred upon ectopic expression of  α -Pal NRF1 . Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides  α -Pal NRF1 . Overall, these across-talks amongst Nfe2l1, Nfe2l2, and  α -Pal NRF1 , 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, much cautions should be severely taken for us to interpret those relevant experimental results obtained from knockout of Nfe2l1, Nfe2l2,  α -Pal or Pitx2, or their gain-of-functional mutants.

oxidative medicine and cellular longevity

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