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, 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.

中文翻译：

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两个不同但混淆的 Nrf1 因子在核到线粒体呼吸和抗氧化转录网络的整体调节中的协同作用和拮抗作用

迄今为止，没有文献可用于解释两种不同但混淆的 Nrf1 转录因子，因为它们共享与核因子红细胞 2 相关因子 1（也称为 Nfe2l1）和核呼吸因子（最初称为α -Pal）的相同缩写。因此，我们在这里确定 Nfe2l1 ^Nrf1和α- Pal ^NRF1在核到线粒体呼吸和抗氧化转录谱的综合调节中发挥协同和拮抗作用。在小鼠胚胎成纤维细胞 (MEF) 中，敲除Nfe2l1 ^-/-导致α -Pal ^{NRF1 的}表达水平显着降低和 Nfe2l2，连同 TFAM（线粒体转录因子 A）和其他靶基因。在Nfe2l2 ^-/- MEF中确定了类似的抑制结果，但GSTa1和Aldh1a1在Nfe2l1 ^-/- MEF 中均显着上调。Nfe2l1 和 Nfe2l2 对α- Pal ^NRF1和 TFAM的正向调节的这种协同作用在Keap1 ^-/- MEF 中得到了验证。然而，人类α -Pal ^{NRF1 的}表达没有被hNfe2l1α ^-/-、hNfe2l2 ^-/-ΔTA甚至hNfe2l1α ^-/- +siNrf2，尽管 TFAM 被 Nfe2l1 激活但被 Nfe2l2 抑制；这种拮抗作用发生在 HepG2 细胞中。相反，几乎所有的小鼠 Nfe2l1、Nfe2l2 和共靶基因在α-Pal ^NRF1+/- MEF 中都被下调。相反，人 Nfe2l1、Nfe2l2 和相关报告基因的上调发生在α- Pal ^NRF1沉默后，但它们的下调发生在α- Pal ^{NRF1 的}异位表达时。此外，除了α- Pal ^NRF1之外，Pitx2（垂体同源盒 2）也被确定为 Nfe2l1 和 TFAM 的直接上游调节器. 总体而言，Nfe2l1、Nfe2l2 和α- Pal ^NRF1以及 Pitx2之间的这些交叉对话从内质网整合到用于靶向 TFAM 的核-线粒体通信，以便微调不同细胞的稳健平衡氧化呼吸和抗氧化基因转录网络，尽管它们在小鼠和人类之间有所不同。此外，至关重要的是要注意，鉴于这些转录因子的这种相互调节，在解释从敲除 Nfe2l1、Nfe2l2、α- Pal 或 Pitx2 中获得的相关实验结果时应该非常谨慎。或它们的功能获得性突变体。