The electron transport chain and oxidative phosphorylation system rely
on the functional interplay of gene products expressed from both nuclear and mitochondrial genomes. Because of the
limited coding capacity of the mitochondrial chromosome, nuclear genes must provide most of the respiratory subunits
and all of the gene products necessary for mitochondrial DNA transcription and replication. Nuclear respiratory
factor-1 (NRF1) is a transcription factor that acts on nuclear genes encoding respiratory subunits and components of the
mitochondrial transcription and replication machinery.
NCBI Summary:
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]
General function
Metabolism
Comment
Cellular localization
Mitochondrial
Comment
Ovarian function
Follicle atresia, Steroid metabolism, Oogenesis
Comment
Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells. Zhang GM et al. (2017) During goat follicular development, abnormal expression of nuclear respiratory factor 1 (NRF1) in granulosa cells may drive follicular atresia with unknown regulatory mechanisms. In this study, we investigated the effects of NRF1 on steroidogenesis and cell apoptosis by overexpressing or silencing it in goat luteinized granulosa cells (LGCs). Results showed that knockdown of NRF1 expression significantly inhibited the expression of STAR and CYP19A1, which are involved in sex steroid hormones synthesis, and led to lower estrogen levels. Knockdown of NRF1 resulted in an increased percentage of apoptosis, probably due to the release of cytochrome c from mitochondria, accompanied by upregulating mRNA and protein levels of apoptosis-related markers BAX, caspase 3 and caspase 9. These data indicate that NRF1 might be related with steroidogenesis and cell apoptosis. Furthermore, NRF1 silence reduced mitochondrial transcription factor A (TFAM) transcription activity, mtDNA copy number and ATP level. Simultaneously, knockdown of NRF1 suppressed the transcription and translation levels of SOD, GPx and CAT, decreased glutathione level and increased 8-OHdG level. However, the overexpression of NRF1 in LGCs or gain of TFAM in NRF1 silenced LGCs increased the expression of genes involved in mitochondrial function and biogenesis, and elevated the antioxidant stress system and steroids synthesis. Taken together, aberrant expression of NRF1 could induce mitochondrial dysfunction and disturb the cellular redox balance, which lead to disturbance of steroid hormone synthesis, and trigger LGC apoptosis through the mitochondria-dependent pathway. These findings will be helpful for understanding the role of NRF1 in goat ovarian follicular development and atresia.//////////////////
Expression regulated by
Steroids
Comment
Abnormal Mitochondrial Function and Impaired Granulosa Cell Differentiation in Androgen Receptor Knockout Mice. Wang RS et al. (2015) In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR-/-) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR-/- mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR-/- female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells.//////////////////
Ovarian localization
Oocyte
Comment
Comparison of Mitochondrial-Related Transcriptional Levels of TFAM, NRF1 and MT-CO1 Genes in Single Human Oocytes at Various Stages of the Oocyte Maturation. Ghaffari Novin M et al. (2015) The aim of the current study was to assess the mRNA levels of two mitochondria-related genes, including nuclear-encoded NRF1 (nuclear respiratory factor 1), mitochondrial transcription factor A (TFAM), and mitochondrial-encoded cytochrome c oxidase subunit 1 (MT-CO1) genes in various stages of the human oocyte maturation. Oocytes were obtained from nine infertile women with male factor undergoing in vitro fertilization (IVF)/intra-cytoplasmic sperm injection protocol. Mitochondrial-related mRNA levels were performed by single-cell TaqMan real-time PCR. the expression level of the target genes was low at the germinal vesicle stage (P>0.05). Although the mRNA level of NRF1gene remained stable in metaphase I, the mRNA level of TFAM and MT-CO1 increased significantly (P<0.05).In metaphase II, the expression level of all genes increased compared to metaphase I (P<0.05). The overexpression levels of NRF1, TFAM, and MT-CO1 genes are related to the oocyte maturation. Therefore, the current study could be used clinically to improve the success rate of IVF.//////////////////
Follicle stages
Antral, Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Huo L, et al 2001 reported mitochondrial DNA instability and peri-implantation lethality
associated with targeted disruption of nuclear respiratory
factor 1 in mice.
In vitro studies have implicated nuclear respiratory factor 1 (NRF-1) in the
transcriptional expression of nuclear genes required for mitochondrial
respiratory function, as well as for other fundamental cellular activities. The authors
investigated here the in vivo function of NRF-1 in mammals by disrupting the
gene in mice. A portion of the NRF-1 gene that encodes the nuclear
localization signal and the DNA-binding and dimerization domains was replaced
through homologous recombination by a beta -galactosidase-neomycin cassette.
In the mutant allele, beta -galactosidase expression is under the control of
the NRF-1 promoter. Embryos homozygous for NRF-1 disruption die between
embryonic days 3.5 and 6.5, beta -Galactosidase staining was observed in
growing oocytes and in 2.5- and 3.5-day-old embryos, demonstrating that the
NRF-1 gene is expressed during oogenesis and during early stages of
embryogenesis. Moreover, the embryonic expression of NRF-1 did not result from
maternal carryover. While most isolated wild-type and NRF-1(+/-) blastocysts
can develop further in vitro, the NRF-1(-/-) blastocysts lack this ability
despite their normal morphology. These results are consistent with a specific requirement for NRF-1
in the maintenance of mtDNA and respiratory chain function during early
embryogenesis.