Nrf1, also known as Nuclear Factor Erythroid 2 Like 1 (Nfe2l1), is a stress-responsive transcription factor. It is involved in multiple crucial functions such as mitochondrial biogenesis, proteostasis, redox balance, cholesterol homeostasis, and regulation of the ubiquitin-proteasome system. It participates in pathways related to innate antiviral immunity, heart regeneration, and responses to various cellular stresses, making it biologically significant [1-3, 6, 10]. Genetic models, especially knockout (KO) mouse models, have been valuable in studying its functions.

In KO mouse models, Nrf1 deficiency led to enhanced innate immunity, decreased viral load, and morbidity in response to RNA (VSV) or DNA (HSV-1) virus infections, suggesting its role in an antiviral negative-feedback loop by modulating mitochondrial biogenesis [1]. In the context of heart regeneration, genetic deletion of Nrf1 prevented neonatal cardiomyocytes from activating the transcriptional program required for heart regeneration [2]. In high-altitude cerebral edema (HACE) mouse models, up-regulated Nrf1 in microglia under hypoxia was found to trigger HACE by promoting inflammatory response and phagocytic function [3].

In conclusion, Nrf1 is essential for maintaining mitochondrial homeostasis, heart regeneration, cholesterol balance, and proteasome biogenesis. Studies using KO mouse models have revealed its significant contributions to diseases like viral infections, heart injury, and HACE. Understanding Nrf1's functions provides insights into disease mechanisms and potential therapeutic targets in these disease areas [1,2,3].

References:

1. Zhao, Tian, Zhang, Jiaojiao, Lei, Hong, Chen, Quan, Zhu, Yushan. 2023. NRF1-mediated mitochondrial biogenesis antagonizes innate antiviral immunity. In The EMBO journal, 42, e113258. doi:10.15252/embj.2022113258. https://pubmed.ncbi.nlm.nih.gov/37409632/

2. Cui, Miao, Atmanli, Ayhan, Morales, Maria Gabriela, Bassel-Duby, Rhonda, Olson, Eric N. 2021. Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance. In Nature communications, 12, 5270. doi:10.1038/s41467-021-25653-w. https://pubmed.ncbi.nlm.nih.gov/34489413/

3. Wang, Xueting, Chen, Guijuan, Wan, Baolan, Lu, Yapeng, Zhu, Li. . NRF1-mediated microglial activation triggers high-altitude cerebral edema. In Journal of molecular cell biology, 14, . doi:10.1093/jmcb/mjac036. https://pubmed.ncbi.nlm.nih.gov/35704676/