NRF1

Official Full Name

nuclear respiratory factor 1

Organism

Homo sapiens

GeneID

4899

Background

This gene encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternative splicing results in multiple transcript variants. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor (erythroid-derived 2)-like 1" which has an official symbol of NFE2L1. [provided by RefSeq, May 2014]

Synonyms

ALPHA-PAL;

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Detailed Information

Nuclear respiratory factor-1 (NRF1) was originally found in the cytochrome C promoter. As a regulatory factor, it regulates cellular energy metabolism and transcription and replication of mitochondrial mtDNA. Besides, several studies have shown that NRF1 plays an important role in maintaining mitochondrial homeostasis in cases of heart failure, cardiomyopathy, and other cardiac cell dysfunction.

NRF1 Figure 1. The mitochondrial bi-directional circuit. NRF1 here is nuclear respiratory factor 1.（Zolotukhin, P. V., et al. 2016）

Molecular Biological Characteristics of NRF1

NRF1 belongs to the nuclear respiratory factor family. NRF1 is an important factor for regulating cell energy metabolism, which can not only regulate the expression of respiratory chain enzyme complex subunits, but also regulate the expression of mitochondrial inner and outer membrane transporter receptor subunits, which plays an important role in regulating the process of cellular mitochondrial oxidation productivity. In addition, it acts as an important nuclear-encoded transcriptional regulator that affects the transcription and replication of mtDNA. Moreover, NRF1 can mediate the coordination between the nuclear and mitochondrial genomes, fight cellular oxidative stress and participate in the biosynthesis of heme. In short, NRF1 can maintain the normal function of mitochondria in various ways. NRF1 is the link between the nuclear genome and the mitochondrial genome, and plays an important role in mitochondrial biosynthesis and respiration. In addition to regulating respiratory function, it also has significance for cell growth, chromosome maintenance, maintaining the excitability of neurons, and enhancing the anti-apoptosis of neurons.

NRF1 and Disease

Cardiomyocytes, as high-energy-consuming cells of the body, require a large amount of energy to supply their huge energy requirements, and mitochondria are places where energy is generated. Studies in neonatal cardiomyocytes found that in order to adapt to an oxygen-rich environment, the mitochondria in the cardiomyocytes changed rapidly, and the number of mitochondria and the complexity of the mitochondrial inner membrane increased. Correspondingly, the expression of NRF1 increased sharply and the expression of HIF decreased. Under hypoxic conditions, overexpression of NRF1 gene is beneficial to cell survival. In addition, the NRF1 gene can improve the hypoxic state of the cell, which may be by increasing cell viability, reducing the level of mitochondrial depolarization, increasing the expression level of anti-apoptotic genes and inhibiting the expression level of pro-apoptotic genes, thereby reducing apoptosis rate. In addition, in vitro drugs stimulate cardiomyocytes, promote up-regulation of NRF1 expression, and increase the expression of mitochondrial oxidative phosphorylated protein. The above research speculates that drugs can increase the expression of NRF1 in heart failure cells through stimulation or transcription, causing the expression of mitochondrial DNA and related proteins to increase. This can maintain the functional stability of myocardial cells, slow down the remodeling of myocardial structure, and extend the survival time of the body.

At present, a large number of studies have shown that mitochondria play a key role in the etiology of familial and sporadic Parkinson's disease (PD), and NRF1 is also an important factor in mitochondrial biosynthesis and function regulation. In MPTP-modeled Parkinson's disease model mice, the expression of NRF1 and TFAM was reduced in the substantia nigra and striatum, and there was no significant change in the cerebellum and cerebral cortex. In SH-SY5 Y Parkinson's cell model, by expressing NRF1 or TFAM can obviously restore MPP+ damage to mitochondria and dopaminergic neurons. Its mechanisms include: increasing mitochondrial complex I activity, restoring mitochondrial membrane potential, increasing ATP levels, reducing ROS production, and increasing the expression of tyrosine hydroxylase (TH).

References:

Zolotukhin, P. V. , & Belanova, A. A. . (2016). Feed-Forward and Feed-Back Circuits of the NRF2/AP-1 Composite Pathway. "A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2.
Yuanshuai, Z. , Zhongjuan, X. , Daniel, Q. , Fan, Z. , Hai, Z. , & Tongqian, X. , et al. (2018). Nuclear respiratory factor 1 promotes spheroid survival and mesenchymal transition in mammary epithelial cells. Oncogene.
Jayanta, K, Das, Quentin, Felty, & Robert., et al. (2018). Nuclear respiratory factor 1 acting as an oncoprotein drives estrogen-induced breast carcinogenesis. Cells, 7(12).

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