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NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13)

Written2015-11Mafalda Pinto, Valdemar Máximo
IPATIMUP Institute of Molecular Pathology and Immunology of the University of Porto, Portugal (MP, VM); I3S - Institute for Innovation and Helath Research, University of Porto, Portugal (MP, VM); Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal (VM);;

Abstract Short communication on NDUFA13, with data on DNA/RNA, on the protein encoded and where this gene is implicated.

Keywords NDUFA13; GRIM-19; mitochondria complex I; apoptosis.

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Other aliasB16.6
complex I B16.6 subunit
LocusID (NCBI) 51079
Atlas_Id 50482
Location 19p13.11 (Chromosome 19: 19,626,545-19,644,285 forward strand.) (Chidambaram et al., 2000).  [Link to chromosome band 19p13]
Location_base_pair Starts at and ends at bp from pter
Local_order Orientation: Forward Strand. Between theGATAD2A and YJEFN3 genes.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
NDUFA13 (19p13.11) / SRRM2 (16p13.3)RPLP0 (12q24.23) / NDUFA13 (19p13.11)


Note NDUFA13 is a protein-coding gene, which encodes a subunit of the mitochondrial respiratory chain NADH dehydrogenase (Complex I).
Description The NDUFA13 gene, with 18995 bases in length (NG_013380), consists 5 exons and 4 introns. It was first identified and isolated by antisense knock-out techniques, in a study aiming the identification of gene products that participate in synergistic growth-suppressive actions (Angell et al., 2000). Expression of NDUFA13 is induced by IFNB1/IFN-beta combined with all-trans-retinoic acid.
Transcription The NDUFA gene is characterized by 7 transcripts. Three are protein coding transcripts. The transcribed mRNA of NDUFA13 gene has 557 bp (NM_015965). RNA is expressed in all tissues. Two other transcripts are protein coding, one with 120 aa and another with 150 aa. Two transcripts are nonsense mediated decay and two other retain an intron, none of these 4 coding for proteins. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N-terminus have been found, but their biological validity has not been determined. (Provided by RefSeq, Oct 2009).


Note Protein class: disease related genes, mitochondrial proteins, predicted membrane proteins.
Description The human NDUFA13 gene encodes for a 16KDa protein and 144 aminoacids, purified from mitochondria. It was first identified as a novel cell death-regulatory gene whose inactivation confers growth advantage to cells in the presence of IFN/RA (Angell et al., 2000). This protein has a modified residue at position 2, an alanine that can be acetylated. The transmembrane portion of NDUFA13 protein encompasses aminoacids at positions 30 to 51, being 22 residues long, and has a helical shape. The 43 aa region consisting of residues 102 to 144, is important for inducing cell death.
Translation (144 aa)
Amino acids: 144. Molecular weight: 16KD. The NDUFA13 gene encodes for a protein that belongs to the family of NADH dehydrogenase ubiquitone 1 alpha subcomplex 13.
  Diagram of the NDUFA13 protein. Numbers indicate amino acids. The box inside represents the transmembrane domain (TM). The domains indicated by the blue key represent sequences for mitochondrial targeting, maintenance of Δψm, and enhancing assembly.
Expression Widely expressed with highest expression in heart, skeletal muscle, liver, kidney and placenta. (Angell et al., 2000) Ubiquitous cytoplasmatic expression with a granular pattern. Membrane.
Localisation Mitochondria inner membrane, Single-pass membrane protein, Matrix side, Nucleus. (UniProt Q9P0J0).
Function Molecular function: catalytic - oxiredutase activity - and it is involved in metabolic processes and biological regulation.
NDUFA13 was described in 2004 as a gene product with a specific role in IFN-RA-induced cell death, as a functional component of mitochondrial complex I and as being essential for early embryonic development (Huang et al., 2004).
Cell death regulatory protein that promotes apoptosis, is a negative regulator of cell growth, and it is involved in mitochondrial metabolism (Angell et al., 2000; Lufei et al., 2003).
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). Involved in the interferon/all-trans-retinoic acid (IFN/RA) induced cell death, which is inhibited by interaction with viral IRF1. Prevents the transactivation of STAT3 target genes (Lufei et al., 2003; Zhang et al., 2003).
Diseases associated with NDUFA13 include thyroid Hürthle cell carcinoma, and kidney cancer. GO annotations related to this gene include NADH dehydrogenase activity and NADH dehydrogenase (ubiquinone) activity.
Homology NDUFA13 score . There are still 120 uncharacterized proteins in different species including Homo sapiens, with homologies varying from 28% to 100% (Homo sapiens). Nine predicted proteins with homologies between 40% and 52% have also been identified in different species (B2014110593WH1M8NCV)


Note Loss of expression and occurrence of mutations in the NDUFA13 gene in a variety of primary human cancers-lung, kidney, prostate, thyroid, ovary, colon, esophagus and brain (Alchanati et al., 2006; Máximo et al., 2008; Zhou et al., 2009; Fan et al., 2012) - have been described, indicating its potential role as tumor suppressor. Depletion or overexpression of NDUFA13 promotes and suppresses, respectively, tumor growth (Angell et al., 2000; Máximo et al., 2008; Huang et al., 2010). Levels of expression of NDUFA13 are a good prognostic marker for colorectal cancer (Hao et al., 2015) and loss of expression correlate with malignancy in Hürthle cell tumours (Donatini et al., 2015).
Germinal One germline missense mutation of NDUFA13 has been identified in one patient with apparently sporadic Hürthle cell carcinoma: G264C substitution in exon 1 (Máximo et al., 2005).
Somatic Three missense mutations have been identified in three out of 20 cases of sporadic Hürthle cell carcinomas: a C77T and a A247G in exon 1, and a G593C in exon 5 (Máximo et al., 2005). Three somatic mutations of NDUFA13 gene have been identified in a set of primary head and neck tumors (Nallar et al., 2013). Wild-type NDUFA13 suppresses cellular transformation by a constitutively active form of STAT3, whereas tumor-derived mutants (L71P, L91P and A95T) significantly lost their ability to associate with STAT3, block gene expression and suppress cell transformation and tumor growth in vivo. These three mutants have also lost their capacity to prevent metastasis.

Implicated in

Entity Various cancers, arthritis and mouse embryo development and implantation.
Disease Renal Cell Carcinomas (RCC), inflammatory bowel diseases, Kaposi sarcoma, Hürthle cell carcinomas, lung cancer, hepatocellular carcinoma, colorectal cancer (CRC), prostate carcinoma, cervical carcinoma, breast carcinomas, head and neck squamous cell carcinoma.
Prognosis NDUFA13 mRNA and protein expression are significantly lower in colorectal cancer than in normal tissues. It is suggested that low NDUFA13 expression is closely associated with colorectal cancer progression and might be a very promising prognostic biomarker for CRC patients (Hao et al., 2015). Moreover, in breast cancers, nonexpression of NDUFA13 is significantly associated with lymph node metastasis, advanced tumor-node-metastasis stage, triple-negative which is a mark of bad prognosis (Zhou et al., 2013).
Entity Embryo development and implantation
Note The expression of NDUFA13 in mouse preimplantation embryos changes at different developmental phases suggesting an important role during embryonic development (Cui et al., 2012). Other authors have seen that downregulation of NDUFA13 affects mouse oocyte viability, maturation and embryo development and implantation (Chao et al., 2015).
Entity Thyroid cancer
Note Somatic and germline mutations, 15% and 5%, respectively, in NDUFA13, were described in Hürthle cell tumors of the thyroid (Máximo et al., 2005). These mutations were described as the first nuclear gene mutations specific to Hürthle cell tumors and it was proposed that such mutations may be involved in the genesis of sporadic as well as familial Hürthle cell tumors through the dual function of NDUFA13 in mitochondria metabolism and cell death.
Entity Renal cell carcinoma
Note NDUFA13 expression is lost or severely decreased in primary RCC (Alchanati et al., 2006). The presence of NDUFA13 protein was evaluated by Western blot in 11 cases of RCC and it was absent, weakly or moderately present in 4, 6 and 1 cases, respectively, compared with normal counterpart (Alchanati et al., 2006). The pattern of mRNA expression correlated with the level of protein expression by Western blot analysis. In the same study, an immunostaining evaluation showed intense nuclear membrane and cytoplasmic staining in proximal tubular epithelium in normal kidney, whereas NDUFA13 expression was absent in 93% of the cases. Downregulation of NDUFA13 is associated with enhanced cell proliferation which is proposed to act via uninhibited STAT3 regulatory pathway (Alchanati et al., 2006).
Entity Prostate cancer
Note NDUFA13 protein expression is not significantly decreased in prostate cancer. Loss of NDUFA13 staining by immunohistochemistry was found in only 2 out of 17 prostate carcinomas (Alchanati et al., 2006).
Entity Kaposi's sarcoma
Note NDUFA13 inhibits INF/retinoic acid-induced cell death (Seo et al., 2002).
Entity Lung cancer
Note There is a negative correlation between the expression level of NDUFA13 and the stage of the primary lesion of non-small cell lung carcinomas (NSCLC). Downregulation of NDUFA13 was described in NSCLC stages III-IV compared to stages I-II (Fan et al., 2012). GRIM-19 is mainly located in the cytoplasm in lung inflammation tissues, but located in the nucleus in lung cancer tissues (Fan et al., 2012).
Entity Hepatocellular carcinoma
Note Expression levels of NDUFA13 are significantly lower in hepatocellular carcinoma patients with deteriorating differentiation states, hepatic capsule invasion and microvascular invasion (Hao et al., 2012).
Entity Gliomas
Note Gliomas express NDUFA13 at low levels and this plays a major role in tumorigenesis of the brain. NDUFA13 mRNA and protein levels are significantly lower in gliomas than in control brain tissues. NDUFA13 expression levels negatively correlates with malignancy of the gliomas (Zhang et al., 2011).
Entity Cervical cancer
Note Zhou et al. have shown that reduction of the levels of NDUFA13 protein occurs in primary cervical cancers, and is associated with hyperactivation of STAT3 (Zhou et al., 2009; Chen et al., 2015).
Entity Breast cancer
Note Nonexpression of NDUFA13 is significantly associated with lymph node metastasis, advanced tumor-node-metastasis stage, triple-negative phenotype and low NDUFA13 expression is correlated with STAT3 overexpression (Zhou et al., 2013).
Entity Colorectal cancer
Note NDUFA13 shows low or absent expression in colorectal carcinomas. mRNA and protein expression are lower in colorectal carcinoma than in normal tissues (Hao et al., 2015).
Entity Head and neck squamous cell carcinoma
Note Decreased expression of NDUFA13 due to hypermethylation is correlated with cell proliferation in head and neck squamous cell carcinoma (Zhang et al., 2015).
Entity Inflamatory bowel disease
Note NDUFA13 expression is decreased in inflamed mucosa of patients with inflammatory bowel disease (Barnich et al., 2005).
Entity Bladder urothelium
Note NDUFA13 protein expression is not significantly decreased in bladder tumors. Loss of NDUFA13 staining by immunohistochemistry was found in only 1 of 6 transitional cell carcinomas of the renal pelvis (Alchanati et al., 2006).
Entity Arthritis
Note NDUFA13 attenuates murine autoimmune arthritis (Moon et al., 2014).


A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas
Alchanati I, Nallar SC, Sun P, Gao L, Hu J, Stein A, Yakirevich E, Konforty D, Alroy I, Zhao X, Reddy SP, Resnick MB, Kalvakolanu DV
Oncogene 2006 Nov 16;25(54):7138-47
PMID 16732315
Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach
Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV
J Biol Chem 2000 Oct 27;275(43):33416-26
PMID 10924506
GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells
Barnich N, Hisamatsu T, Aguirre JE, Xavier R, Reinecker HC, Podolsky DK
J Biol Chem 2005 May 13;280(19):19021-6
PMID 15753091
Downregulation of gene expression and activity of GRIM-19 affects mouse oocyte viability, maturation, embryo development and implantation
Chao L, Wang X, Yang Y, Cui W, Xu J, Chen H, Hao A, Deng X
J Assist Reprod Genet 2015 Mar;32(3):461-70
PMID 25561158
Expression of GW112 and GRIM-19 in colorectal cancer tissues
Chen H, Wu Q
J BUON 2015 Mar-Apr;20(2):438-42
PMID 26011333
Chromosomal localization of human GRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death
Chidambaram NV, Angell JE, Ling W, Hofmann ER, Kalvakolanu DV
J Interferon Cytokine Res 2000 Jul;20(7):661-5
PMID 10926209
Expression of gene associated with retinoid-interferon-induced mortality-19 in preimplantation embryo of mice
Cui WJ, Chao L, Deng XH, Shen YJ, Yang F, Feng WJ, Xu J, Chen HL
Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2012 Jun;34(3):212-5
PMID 22776651
Thyroid Hürthle cell tumors: research of potential markers of malignancy
Donatini G, Beaulieu A, Castagnet M, Kraimps JL, Levillain P, Fromont G
J Endocrinol Invest 2016 Feb;39(2):153-8
PMID 26188382
Expression and clinical significance of GRIM-19 in lung cancer
Fan XY, Jiang ZF, Cai L, Liu RY
Med Oncol 2012 Dec;29(5):3183-9
PMID 22573109
Depletion of GRIM-19 accelerates hepatocellular carcinoma invasion via inducing EMT and loss of contact inhibition
Hao H, Liu J, Liu G, Guan D, Yang Y, Zhang X, Cao X, Liu Q
J Cell Physiol 2012 Mar;227(3):1212-9
PMID 22105514
GRIM-19 expression is a potent prognostic marker in colorectal cancer
Hao M, Shu Z, Sun H, Sun R, Wang Y, Liu T, Ji D, Cong X
Hum Pathol 2015 Dec;46(12):1815-20
PMID 26363526
GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I
Huang G, Lu H, Hao A, Ng DC, Ponniah S, Guo K, Lufei C, Zeng Q, Cao X
Mol Cell Biol 2004 Oct;24(19):8447-56
Upregulation of the GRIM-19 gene suppresses invasion and metastasis of human gastric cancer SGC-7901 cell line
Huang Y, Yang M, Yang H, Zeng Z
Exp Cell Res 2010 Aug 1;316(13):2061-70
PMID 20478305
GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction
Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, Cao X
EMBO J 2003 Mar 17;22(6):1325-35
PMID 12628925
GRIM-19 in Health and Disease
Máximo V, Lima J, Soares P, Silva A, Bento I, Sobrinho-Simõ M
Adv Anat Pathol 2008 Jan;15(1):46-53
PMID 18156812
Gene associated with retinoid-interferon-induced mortality 19 attenuates murine autoimmune arthritis by regulation of th17 and treg cells
Moon YM, Lee J, Lee SY, Her YM, Ryu JG, Kim EK, Son HJ, Kwok SK, Ju JH, Yang CW, Park SH, Kim HY, Cho ML
Arthritis Rheumatol 2014 Mar;66(3):569-78
PMID 24574216
Tumor-derived mutations in the gene associated with retinoid interferon-induced mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis
Nallar SC, Kalakonda S, Lindner DJ, Lorenz RR, Lamarre E, Weihua X, Kalvakolanu DV
J Biol Chem 2013 Mar 15;288(11):7930-41
PMID 23386605
Viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus interacts with a cell death regulator, GRIM19, and inhibits interferon/retinoic acid-induced cell death
Seo T, Lee D, Shim YS, Angell JE, Chidambaram NV, Kalvakolanu DV, Choe J
J Virol 2002 Sep;76(17):8797-807
PMID 12163600
The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3
Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, Poli V, Stark GR, Kalvakolanu DV
Proc Natl Acad Sci U S A 2003 Aug 5;100(16):9342-7
PMID 12867595
Decreased expression of GRIM-19 by DNA hypermethylation promotes aerobic glycolysis and cell proliferation in head and neck squamous cell carcinoma
Zhang XY, Li M, Sun K, Chen XJ, Meng J, Wu L, Zhang P, Tong X, Jiang WW
Oncotarget 2015 Jan 1;6(1):101-15
PMID 25575809
Downregulation of GRIM-19 promotes growth and migration of human glioma cells
Zhang Y, Hao H, Zhao S, Liu Q, Yuan Q, Ni S, Wang F, Liu S, Wang L, Hao A
Cancer Sci 2011 Nov;102(11):1991-9
PMID 21827581
Down-regulation of GRIM-19 is associated with STAT3 overexpression in breast carcinomas
Zhou T, Chao L, Rong G, Wang C, Ma R, Wang X
Hum Pathol 2013 Sep;44(9):1773-9
PMID 23618357
Down-regulation of GRIM-19 expression is associated with hyperactivation of STAT3-induced gene expression and tumor growth in human cervical cancers
Zhou Y, Li M, Wei Y, Feng D, Peng C, Weng H, Ma Y, Bao L, Nallar S, Kalakonda S, Xiao W, Kalvakolanu DV, Ling B
J Interferon Cytokine Res 2009 Oct;29(10):695-703
PMID 19642906


This paper should be referenced as such :
Mafalda Pinto, Valdemar Mximo
NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13)
Atlas Genet Cytogenet Oncol Haematol. 2016;20(8):431-436.
Free journal version : [ pdf ]   [ DOI ]
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External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)51079
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
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canSAR (ICR) (select the gene name)
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