nuclear respiratory factors


Summary: A family of transcription factors that control expression of a variety of nuclear GENES encoding proteins that function in the RESPIRATORY CHAIN of the MITOCHONDRIA.

Top Publications

  1. Baar K. Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise. Proc Nutr Soc. 2004;63:269-73 pubmed
    ..The first group comprises transcription factors such as nuclear respiratory factors (NRF) 1 and 2 and PPAR alpha that bind DNA in a sequence-specific manner...
  2. Gleyzer N, Vercauteren K, Scarpulla R. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol. 2005;25:1354-66 pubmed
    ..Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis...
  3. Virbasius J, Scarpulla R. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A. 1994;91:1309-13 pubmed
    ..that the proximal promoter of the human mtTFA gene is highly dependent upon recognition sites for the nuclear respiratory factors, NRF-1 and NRF-2, for activity...
  4. Scarpulla R. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta. 2002;1576:1-14 pubmed
    ..The interplay of these nuclear factors appears to be a major determinant in regulating the biogenesis of mitochondria. ..
  5. Gugneja S, Virbasius C, Scarpulla R. Nuclear respiratory factors 1 and 2 utilize similar glutamine-containing clusters of hydrophobic residues to activate transcription. Mol Cell Biol. 1996;16:5708-16 pubmed
    b>Nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2) are ubiquitous transcription factors that have been implicated in the control of nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and ..
  6. Au H, Scheffler I. Promoter analysis of the human succinate dehydrogenase iron-protein gene--both nuclear respiratory factors NRF-1 and NRF-2 are required. Eur J Biochem. 1998;251:164-74 pubmed
    ..gene analysis of the human SDH2 promoter indicates that it is transcriptionally regulated by the nuclear respiratory factors NRF-1 and NRF-2...
  7. Burkhardt C, Neuwirth C, Sommacal A, Andersen P, Weber M. Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients. PLoS ONE. 2017;12:e0177555 pubmed publisher
    ..01). The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV. ..
  8. Puigserver P, Rhee J, Lin J, Wu Z, Yoon J, Zhang C, et al. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell. 2001;8:971-82 pubmed
    ..These data illustrate a direct thermogenic action of cytokines and p38 MAP kinase through the transcriptional coactivator PGC-1. ..
  9. Fazio I, Bolger T, Gill G. Conserved regions of the Drosophila erect wing protein contribute both positively and negatively to transcriptional activity. J Biol Chem. 2001;276:18710-6 pubmed
    ..The strong conservation of elements that determine transcriptional activity suggests that the EWG, NRF-1, and P3A2 family of proteins shares common mechanisms of action and has maintained common functions across evolution. ..

More Information


  1. Yang H, Magilnick N, Lee C, Kalmaz D, Ou X, Chan J, et al. Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1. Mol Cell Biol. 2005;25:5933-46 pubmed
    ..In conclusion, Nrf1 and Nrf2 regulate rat GCLC promoter by modulating the expression of key AP-1 and NF-kappaB family members. ..
  2. Murray J, Johnson D. The Cdc42p GTPase and its regulators Nrf1p and Scd1p are involved in endocytic trafficking in the fission yeast Schizosaccharomyces pombe. J Biol Chem. 2001;276:3004-9 pubmed
    ..These data are consistent with Nrf1p and Scd1p being necessary for efficient endocytosis, possibly through the regulation of Cdc42p. ..
  3. Solecki D, Bernhardt G, Lipp M, Wimmer E. Identification of a nuclear respiratory factor-1 binding site within the core promoter of the human polio virus receptor/CD155 gene. J Biol Chem. 2000;275:12453-62 pubmed
    ..We propose that NRF-1, which has been shown by others to be expressed during embryogenesis in animal systems, may be involved in regulating the expression of CD155 at specific stages of central nervous system development. ..
  4. Efiok B, Chiorini J, Safer B. A key transcription factor for eukaryotic initiation factor-2 alpha is strongly homologous to developmental transcription factors and may link metabolic genes to cellular growth and development. J Biol Chem. 1994;269:18921-30 pubmed
    ..Such data suggest that alpha-Pal also functions to modulate the transcription of metabolic genes required for cellular growth. ..
  5. Moyes C, Battersby B, Leary S. Regulation of muscle mitochondrial design. J Exp Biol. 1998;201:299-307 pubmed
  6. Chen S, Nagy P, Zalkin H. Role of NRF-1 in bidirectional transcription of the human GPAT-AIRC purine biosynthesis locus. Nucleic Acids Res. 1997;25:1809-16 pubmed
    ..The decreased expression was accounted for by point mutations in an NRF-1 site and either of two flanking sites for Sp1. These transcription factors account in part for the coordinated expression of human GPAT and AIRC. ..
  7. Li B, Holloszy J, Semenkovich C. Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells. J Biol Chem. 1999;274:17534-40 pubmed
    ..These data suggest that the transcription factor NRF-1 plays a key role in cellular adaptation to energy demands by translating physiological signals into an increased capacity for generating energy. ..
  8. Choi Y, Lee K, Pak Y. Regulation of mitochondrial transcription factor A expression by high glucose. Ann N Y Acad Sci. 2004;1011:69-77 pubmed
    ..It was concluded that high glucose-induced Tfam transcription in L6 cells might be mediated by NRF-1. ..
  9. Chang W, Huang A. Alpha-Pal/NRF-1 regulates the promoter of the human integrin-associated protein/CD47 gene. J Biol Chem. 2004;279:14542-50 pubmed
    ..These results revealed that alpha-Pal/NRF-1 is an essential transcription factor in the regulation of human IAP gene expression. ..
  10. Savagner F, Mirebeau D, Jacques C, Guyetant S, Morgan C, Franc B, et al. PGC-1-related coactivator and targets are upregulated in thyroid oncocytoma. Biochem Biophys Res Commun. 2003;310:779-84 pubmed
    ..However, no mtDNA variant in the D-loop region appeared to be involved in oncocytic development. We conclude that overexpression of the PRC pathway is responsible for mitochondrial proliferation in the context of thyroid oncocytoma...
  11. Pilegaard H, Saltin B, Neufer P. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol. 2003;546:851-8 pubmed
    ..Consistent with its role as a transcriptional coactivator, these findings suggest that PGC-1alpha may coordinate the activation of metabolic genes in human muscle in response to exercise. ..
  12. Tiranti V, Rossi E, Rocchi M, DiDonato S, Zuffardi O, Zeviani M. The gene (NFE2L1) for human NRF-1, an activator involved in nuclear-mitochondrial interactions, maps to 7q32. Genomics. 1995;27:555-7 pubmed
  13. Virbasius C, Virbasius J, Scarpulla R. NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev. 1993;7:2431-45 pubmed
    ..The DNA-binding domain in these molecules is unrelated to motifs found commonly in DNA-binding proteins; thus, NRF-1, P3A2, and EWG represent the founding members of a new class of highly conserved sequence-specific regulatory factors. ..
  14. Holderman M, Miller K, Dangott L, Ramos K. Identification of albumin precursor protein, Phi AP3, and alpha-smooth muscle actin as novel components of redox sensing machinery in vascular smooth muscle cells. Mol Pharmacol. 2002;61:1174-83 pubmed
  15. LeMoine C, McClelland G, Lyons C, Mathieu Costello O, Moyes C. Control of mitochondrial gene expression in the aging rat myocardium. Biochem Cell Biol. 2006;84:191-8 pubmed
    ..Collectively, these data suggest that aging causes complex changes in the enzymes of myocardial energy metabolism, triggered in part by NRF-independent pathways as well as post-transcriptional regulation. ..
  16. Lezza A, Pesce V, Cormio A, Fracasso F, Vecchiet J, Felzani G, et al. Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects. FEBS Lett. 2001;501:74-8 pubmed
    ..The upregulation of TFAM and NRF-1, in aged skeletal muscle, appears involved in the pathway leading to the age-related increase of mitochondrial DNA content. ..
  17. Lowell B, Spiegelman B. Towards a molecular understanding of adaptive thermogenesis. Nature. 2000;404:652-60 pubmed
    ..Here we explore these developments in relation to classical physiological views of adaptive thermogenesis. ..
  18. Becker T, Burgess S, Amsterdam A, Allende M, Hopkins N. not really finished is crucial for development of the zebrafish outer retina and encodes a transcription factor highly homologous to human Nuclear Respiratory Factor-1 and avian Initiation Binding Repressor. Development. 1998;125:4369-78 pubmed
    ..This demonstrates the power of insertional mutagenesis as a means for characterizing novel genes necessary for vertebrate retinal development. ..
  19. Yu L, Yang S. AMP-activated protein kinase mediates activity-dependent regulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha and nuclear respiratory factor 1 expression in rat visual cortical neurons. Neuroscience. 2010;169:23-38 pubmed publisher
    ..These results strongly indicate that AMPK is an essential upstream mediator that couples neuronal activity to mitochondrial energy metabolism by regulation of PGC-1alpha-NRF-1 pathway in neurons. ..
  20. Hayes J, McMahon M. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett. 2001;174:103-13 pubmed
    ..The role of protein kinases in transducing chemical stress signals to the bZIP factors that affect gene induction through the ARE is discussed. ..
  21. Kumari D, Gabrielian A, Wheeler D, Usdin K. The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter. Biochem J. 2005;386:297-303 pubmed
    ..We can reconcile these observations with the positive effect of Sp1 and Sp3 if protein-induced bending acts, at least in part, to bring together distally spaced factors important for transcription initiation. ..
  22. Patti M, Butte A, Crunkhorn S, Cusi K, Berria R, Kashyap S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100:8466-71 pubmed
    ..Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM. ..
  23. Chen L, Kwong M, Lu R, Ginzinger D, Lee C, Leung L, et al. Nrf1 is critical for redox balance and survival of liver cells during development. Mol Cell Biol. 2003;23:4673-86 pubmed
    ..Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development. ..
  24. Vasiliou V, Qamar L, Pappa A, Sophos N, Petersen D. Involvement of the electrophile responsive element and p53 in the activation of hepatic stellate cells as a response to electrophile menadione. Arch Biochem Biophys. 2003;413:164-71 pubmed
    ..This resistance may be a part of the activation process of the hepatic stellate cells and could contribute to their increased proliferation and production of extracellular matrix. ..
  25. Ojuka E, Jones T, Han D, Chen M, Holloszy J. Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J. 2003;17:675-81 pubmed
    ..They support the hypothesis that an increase in cytosolic Ca2+ is one of the signals that mediate increased mitochondrial biogenesis in muscle. ..
  26. Grasberger H, Ye H, Mashima H, Bell G. Dual promoter structure of ZFP106: regulation by myogenin and nuclear respiratory factor-1. Gene. 2005;344:143-59 pubmed
    ..Our results suggest distinct roles of tissue-specific ZFP106 isoforms in growth related metabolism and provide the foundation for further studies into the regulation and function of ZFP106. ..
  27. Annereau J, Ko Y, Pedersen P. Cystic fibrosis transmembrane conductance regulator: the NBF1+R (nucleotide-binding fold 1 and regulatory domain) segment acting alone catalyses a Co2+/Mn2+/Mg2+-ATPase activity markedly inhibited by both Cd2+ and the transition-state analogue orthov. Biochem J. 2003;371:451-62 pubmed
  28. Jacquot C, Lanco X, Carbonnelle D, Sevestre O, Tomasoni C, Briad G, et al. Effect of four genes (ALDH1, NRF1, JAM and KBL) on proliferation arrest in a non-small cell bronchopulmonary cancer line. Anticancer Res. 2002;22:2229-35 pubmed
    ..An antisense strategy showed that amino-ketobutyrate ligase is involved in the proliferation arrest of NSCLC-N6 cells in the G1-phase after VT1 treatment. ..
  29. Sheng B, Wang X, Su B, Lee H, Casadesus G, Perry G, et al. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease. J Neurochem. 2012;120:419-29 pubmed publisher
    ..Overall, this study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD. ..
  30. Terui K, Takahashi Y, Kitazawa J, Toki T, Yokoyama M, Ito E. Expression of transcription factors during megakaryocytic differentiation of CD34+ cells from human cord blood induced by thrombopoietin. Tohoku J Exp Med. 2000;192:259-73 pubmed
    ..The dynamic changes in the levels of different transcription factors that occur during primary megakaryocytic differentiation suggest that the levels of these factors may influence the progression to specific hematopoietic pathways. ..
  31. Felty Q, Xiong W, Sun D, Sarkar S, Singh K, Parkash J, et al. Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. Biochemistry. 2005;44:6900-9 pubmed
  32. Sano M, Wang S, Shirai M, Scaglia F, Xie M, Sakai S, et al. Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO J. 2004;23:3559-69 pubmed
    ..Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy. ..
  33. Chang W, Chen H, Chiou R, Chen C, Huang A. A novel function of transcription factor alpha-Pal/NRF-1: increasing neurite outgrowth. Biochem Biophys Res Commun. 2005;334:199-206 pubmed
    ..These findings indicate that a novel function of alpha-Pal/NRF-1 is to regulate neuronal differentiation, and that this function is mediated partly via its downstream IAP gene. ..
  34. Xu Z, Chen L, Leung L, Yen T, Lee C, Chan J. Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci U S A. 2005;102:4120-5 pubmed
    ..Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer. ..
  35. Morrish F, Giedt C, Hockenbery D. c-MYC apoptotic function is mediated by NRF-1 target genes. Genes Dev. 2003;17:240-55 pubmed
    ..These results suggest that c-myc expression leads to mitochondrial dysfunction and apoptosis by deregulating genes involved in mitochondrial function. ..
  36. Chan J, Cheung M, Moi P, Chan K, Kan Y. Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Hum Genet. 1995;95:265-9 pubmed
    ..3, whereas Nrf1 and 2 mapped to 17q21.3 and 2q31, respectively. However, these three genes were probably derived from a single ancestor by chromosomal duplication as other genes that also map in these regions are related to one another. ..
  37. Suliman H, Carraway M, Welty Wolf K, Whorton A, Piantadosi C. Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1. J Biol Chem. 2003;278:41510-8 pubmed
    ..NRF-1 expression and growth were restored by exogenous oxidant exposure indicating that oxidative stress stimulates biogenesis in part via NRF-1 activation and corresponding to recovery events after LPS-induced liver damage. ..
  38. Elbehti Green A, Au H, Mascarello J, Ream Robinson D, Scheffler I. Characterization of the human SDHC gene encoding of the integral membrane proteins of succinate-quinone oxidoreductase in mitochondria. Gene. 1998;213:133-40 pubmed
    ..Several potential sites for the nuclear respiratory factors NRF-1 and NRF-2 were identified.
  39. Miranda S, Foncea R, Guerrero J, Leighton F. Oxidative stress and upregulation of mitochondrial biogenesis genes in mitochondrial DNA-depleted HeLa cells. Biochem Biophys Res Commun. 1999;258:44-9 pubmed
  40. Rodriguez Jato S, Shan J, Khadake J, Heggestad A, Ma X, Johnstone K, et al. Regulatory elements associated with paternally-expressed genes in the imprinted murine Angelman/Prader-Willi syndrome domain. PLoS ONE. 2013;8:e52390 pubmed publisher
    ..Analysis of transcription factor binding within multiple DH sites detected nuclear respiratory factors (NRF's) and YY1 specifically on the paternal allele...
  41. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science. 2003;299:896-9 pubmed
    ..Thus, a nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance. ..
  42. Thau N, Knippenberg S, K├Ârner S, Rath K, Dengler R, Petri S. Decreased mRNA expression of PGC-1? and PGC-1?-regulated factors in the SOD1G93A ALS mouse model and in human sporadic ALS. J Neuropathol Exp Neurol. 2012;71:1064-74 pubmed publisher
    ..regulation of mitochondrial metabolism and biogenesis via activation of transcription factors, such as nuclear respiratory factors 1 and 2 and mitochondrial transcription factor A (Tfam)...
  43. Rimbach G, Gohil K, Matsugo S, Moini H, Saliou C, Virgili F, et al. Induction of glutathione synthesis in human keratinocytes by Ginkgo biloba extract (EGb761). Biofactors. 2001;15:39-52 pubmed
  44. Kumari D, Usdin K. Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. Implications for Fragile X mental retardation syndrome. J Biol Chem. 2001;276:4357-64 pubmed
    ..This suggests that for efficient reactivation of the FMR1 promoter, significant demethylation must occur and that current approaches to gene reactivation using histone deacetylase inhibitors alone may therefore have limited effect. ..
  45. Kherrouche Z, De Launoit Y, Monte D. The NRF-1/alpha-PAL transcription factor regulates human E2F6 promoter activity. Biochem J. 2004;383:529-36 pubmed
    ..Our results indicate that NRF-1/alpha-PAL is implicated in the regulation of basal E2F6 gene expression. ..
  46. Mercy L, Pauw A, Payen L, Tejerina S, Houbion A, Demazy C, et al. Mitochondrial biogenesis in mtDNA-depleted cells involves a Ca2+-dependent pathway and a reduced mitochondrial protein import. FEBS J. 2005;272:5031-55 pubmed
    ..Taken together, these results suggest that mitochondrial biogenesis is stimulated in mtDNA-depleted cells and involves a calcium-CREB signalling pathway but is associated with a reduced mitochondrial import for matrix proteins. ..
  47. Chowanadisai W, Bauerly K, Tchaparian E, Wong A, Cortopassi G, Rucker R. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression. J Biol Chem. 2010;285:142-52 pubmed publisher
    ..The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. ..
  48. Novotny V, Prieschl E, Csonga R, Fabjani G, Baumruker T. Nrf1 in a complex with fosB, c-jun, junD and ATF2 forms the AP1 component at the TNF alpha promoter in stimulated mast cells. Nucleic Acids Res. 1998;26:5480-5 pubmed
    ..Expression of this altered binding/interaction domain interferes with TNFalpha induction, indicating an interaction of this splice variant with the active AP1/NF-AT complex at this promoter. ..
  49. Huo L, Scarpulla R. Multiple 5'-untranslated exons in the nuclear respiratory factor 1 gene span 47 kb and contribute to transcript heterogeneity and translational efficiency. Gene. 1999;233:213-24 pubmed
    ..Thus, the unusually high sequence conservation within UTR1 in part reflects selective constraints on translational expression. ..
  50. Huo L, Scarpulla R. Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol Cell Biol. 2001;21:644-54 pubmed
    ..These results are consistent with a specific requirement for NRF-1 in the maintenance of mtDNA and respiratory chain function during early embryogenesis. ..
  51. Hertel M, Braun S, Durka S, Alzheimer C, Werner S. Upregulation and activation of the Nrf-1 transcription factor in the lesioned hippocampus. Eur J Neurosci. 2002;15:1707-11 pubmed
    ..Because Nrf-1 and Nrf-2 are potent inducers of various cytoprotective proteins, our data suggest a role of Nrf-1 and Nrf-2 in neuronal survival after acute brain injury. ..
  52. Tokusumi Y, Zhou S, Takada S. Nuclear respiratory factor 1 plays an essential role in transcriptional initiation from the hepatitis B virus x gene promoter. J Virol. 2004;78:10856-64 pubmed
    ..Simultaneous activation of the X gene and mitochondrial genes by NRF1 may allow the X protein to target mitochondria most efficiently. ..
  53. Norrbom J, Sundberg C, Ameln H, Kraus W, Jansson E, Gustafsson T. PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol (1985). 2004;96:189-94 pubmed
    ..This suggests that calcineurin may be activated by exercise in humans and does not exclude that calcineurin could play a role in PGC-1 transcription activation in human skeletal muscle. ..