Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Gene Section Review

NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Mafalda 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); [email protected]; [email protected]

Published in Atlas Database: November 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/NDUFA13ID50482ch19p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66061/11-2015-NDUFA13ID50482ch19p13.pdf DOI: 10.4267/2042/66061 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Location: 19p13.11 ( 19: 19,626,545- 19,644,285 forward strand.) (Chidambaram et al., Short communication on NDUFA13, with data on 2000). DNA/RNA, on the protein encoded and where this Location () : Starts at 19515989 and ends is implicated. at 19528126 bp (according to COSMIC) Keywords Local order: Orientation: Forward Strand. Between NDUFA13; GRIM-19; mitochondria complex I; theGATAD2A and YJEFN3 . . DNA/RNA Identity Note Other names: B16.6, CDA016, CGI-39, GRIM-19, NDUFA13 is a protein-coding gene, which encodes GRIM19, complex I B16.6 subunit a subunit of the mitochondrial respiratory chain HGNC (Hugo): NDUFA13 NADH dehydrogenase (Complex I).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 431 NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Pinto M, Máximo V.

Description Description The NDUFA13 gene, with 18995 bases in length The human NDUFA13 gene encodes for a 16KDa (NG_013380), consists 5 exons and 4 introns. It was protein and 144 aminoacids, purified from first identified and isolated by antisense knock-out mitochondria. techniques, in a study aiming the identification of It was first identified as a novel cell death-regulatory gene products that participate in synergistic growth- gene whose inactivation confers growth advantage to suppressive actions (Angell et al., 2000). Expression cells in the presence of IFN/RA (Angell et al., 2000). of NDUFA13 is induced by IFNB1/IFN-beta This protein has a modified residue at position 2, an combined with all-trans-retinoic acid. alanine that can be acetylated. Transcription The transmembrane portion of NDUFA13 protein encompasses aminoacids at positions 30 to 51, being The NDUFA gene is characterized by 7 transcripts. 22 residues long, and has a helical shape. Three are protein coding transcripts. The transcribed The 43 aa region consisting of residues 102 to 144, mRNA of NDUFA13 gene has 557 bp is important for inducing cell death. (NM_015965). RNA is expressed in all tissues. Two Translation (144 aa) other transcripts are protein coding, one with 120 aa Amino acids: 144. Molecular weight: 16KD. The and another with 150 aa. Two transcripts are NDUFA13 gene encodes for a protein that belongs nonsense mediated decay and two other retain an to the family of NADH dehydrogenase ubiquitone 1 intron, none of these 4 coding for proteins. alpha subcomplex 13. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N- Expression terminus have been found, but their biological Widely expressed with highest expression in heart, validity has not been determined. (Provided by skeletal muscle, liver, kidney and placenta. (Angell RefSeq, Oct 2009). et al., 2000) Ubiquitous cytoplasmatic expression with a granular pattern. Membrane. Protein Localisation Note Mitochondria inner membrane, Single-pass Protein class: disease related genes, mitochondrial membrane protein, Matrix side, Nucleus. (UniProt proteins, predicted membrane proteins. Q9P0J0).

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.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 432

NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Pinto M, Máximo V.

Function species (B2014110593WH1M8NCV) Molecular function: catalytic - oxiredutase activity - and it is involved in metabolic processes and biological regulation. Mutations NDUFA13 was described in 2004 as a gene product Loss of expression and occurrence of mutations in with a specific role in IFN-RA-induced cell death, as the NDUFA13 gene in a variety of primary human a functional component of mitochondrial complex I cancers-lung, kidney, prostate, thyroid, ovary, colon, and as being essential for early embryonic esophagus and brain (Alchanati et al., 2006; Máximo development (Huang et al., 2004). et al., 2008; Zhou et al., 2009; Fan et al., 2012) - have Cell death regulatory protein that promotes been described, indicating its potential role as tumor apoptosis, is a negative regulator of cell growth, and suppressor. it is involved in mitochondrial metabolism (Angell Depletion or overexpression of NDUFA13 promotes et al., 2000; Lufei et al., 2003). and suppresses, respectively, tumor growth (Angell Accessory subunit of the mitochondrial membrane et al., 2000; Máximo et al., 2008; Huang et al., 2010). respiratory chain NADH dehydrogenase (Complex Levels of expression of NDUFA13 are a good I). Involved in the /all-trans-retinoic acid prognostic marker for colorectal cancer (Hao et al., (IFN/RA) induced cell death, which is inhibited by 2015) and loss of expression correlate with interaction with viral IRF1. Prevents the malignancy in Hürthle cell tumours (Donatini et al., transactivation of STAT3 target genes (Lufei et al., 2015). 2003; Zhang et al., 2003). Diseases associated with NDUFA13 include thyroid Germinal Hürthle cell carcinoma, and kidney cancer. GO One germline missense mutation of NDUFA13 has annotations related to this gene include NADH been identified in one patient with apparently dehydrogenase activity and NADH dehydrogenase sporadic Hürthle cell carcinoma: G264C substitution (ubiquinone) activity. in exon 1 (Máximo et al., 2005). Homology Somatic NDUFA13 score. Three missense mutations have been identified in There are still 120 uncharacterized proteins in three out of 20 cases of sporadic Hürthle cell different species including Homo sapiens, with carcinomas: a C77T and a A247G in exon 1, and a homologies varying from 28% to 100% (Homo G593C in exon 5 (Máximo et al., 2005). sapiens). Three somatic mutations of NDUFA13 gene have Nine predicted proteins with homologies between been identified in a set of primary head and neck 40% and 52% have also been identified in different tumors (Nallar et al., 2013).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 433

NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Pinto M, Máximo V.

Wild-type NDUFA13 suppresses cellular and might be a very promising prognostic biomarker transformation by a constitutively active form of for CRC patients (Hao et al., 2015). STAT3, whereas tumor-derived mutants (L71P, Moreover, in breast cancers, nonexpression of L91P and A95T) significantly lost their ability to NDUFA13 is significantly associated with lymph associate with STAT3, block and node metastasis, advanced tumor-node-metastasis suppress cell transformation and tumor growth in stage, triple-negative which is a mark of bad vivo. prognosis (Zhou et al., 2013). These three mutants have also lost their capacity to prevent metastasis. Embryo development and implantation Implicated in The expression of NDUFA13 in mouse preimplantation embryos changes at different Various cancers, arthritis and mouse developmental phases suggesting an important role embryo development and during embryonic development (Cui et al., 2012). implantation. Other authors have seen that downregulation of NDUFA13 affects mouse oocyte viability, Disease maturation and embryo development and Renal Cell Carcinomas (RCC), inflammatory bowel implantation (Chao et al., 2015). diseases, Kaposi sarcoma, Hürthle cell carcinomas, lung cancer, hepatocellular carcinoma, colorectal Thyroid cancer cancer (CRC), prostate carcinoma, cervical Somatic and germline mutations, 15% and 5%, carcinoma, breast carcinomas, head and neck respectively, in NDUFA13, were described in squamous cell carcinoma. Hürthle cell tumors of the thyroid (Máximo et al., Prognosis 2005). These mutations were described as the first NDUFA13 mRNA and protein expression are nuclear gene mutations specific to Hürthle cell significantly lower in colorectal cancer than in tumors and it was proposed that such mutations may normal tissues. be involved in the genesis of sporadic as well as It is suggested that low NDUFA13 expression is familial Hürthle cell tumors through the dual closely associated with colorectal cancer progression function of NDUFA13 in mitochondria metabolism and cell death.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 434

NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Pinto M, Máximo V.

Renal cell carcinoma cancers, and is associated with hyperactivation of STAT3 (Zhou et al., 2009; Chen et al., 2015). NDUFA13 expression is lost or severely decreased in primary RCC (Alchanati et al., 2006). The Breast cancer presence of NDUFA13 protein was evaluated by Nonexpression of NDUFA13 is significantly Western blot in 11 cases of RCC and it was absent, associated with lymph node metastasis, advanced weakly or moderately present in 4, 6 and 1 cases, tumor-node-metastasis stage, triple-negative respectively, compared with normal counterpart phenotype and low NDUFA13 expression is (Alchanati et al., 2006). The pattern of mRNA correlated with STAT3 overexpression (Zhou et al., expression correlated with the level of protein 2013). expression by Western blot analysis. In the same study, an immunostaining evaluation showed intense Colorectal cancer nuclear membrane and cytoplasmic staining in NDUFA13 shows low or absent expression in proximal tubular epithelium in normal kidney, colorectal carcinomas. mRNA and protein whereas NDUFA13 expression was absent in 93% of expression are lower in colorectal carcinoma than in the cases. Downregulation of NDUFA13 is normal tissues (Hao et al., 2015). associated with enhanced cell proliferation which is Head and neck squamous cell proposed to act via uninhibited STAT3 regulatory pathway (Alchanati et al., 2006). carcinoma Prostate cancer Decreased expression of NDUFA13 due to hypermethylation is correlated with cell proliferation NDUFA13 protein expression is not significantly in head and neck squamous cell carcinoma (Zhang et decreased in prostate cancer. Loss of NDUFA13 al., 2015). staining by immunohistochemistry was found in only 2 out of 17 prostate carcinomas (Alchanati et Inflamatory bowel disease al., 2006). NDUFA13 expression is decreased in inflamed Kaposi's sarcoma mucosa of patients with inflammatory bowel disease (Barnich et al., 2005). NDUFA13 inhibits INF/retinoic acid-induced cell death (Seo et al., 2002). Bladder urothelium Lung cancer NDUFA13 protein expression is not significantly decreased in bladder tumors. Loss of NDUFA13 There is a negative correlation between the staining by immunohistochemistry was found in expression level of NDUFA13 and the stage of the only 1 of 6 transitional cell carcinomas of the renal primary lesion of non-small cell lung carcinomas pelvis (Alchanati et al., 2006). (NSCLC). Downregulation of NDUFA13 was described in NSCLC stages III-IV compared to Arthritis stages I-II (Fan et al., 2012). GRIM-19 is mainly NDUFA13 attenuates murine autoimmune arthritis located in the cytoplasm in lung inflammation (Moon et al., 2014). tissues, but located in the nucleus in lung cancer tissues (Fan et al., 2012). References Hepatocellular carcinoma Alchanati I, Nallar SC, Sun P, Gao L, Hu J, Stein A, Expression levels of NDUFA13 are significantly Yakirevich E, Konforty D, Alroy I, Zhao X, Reddy SP, Resnick MB, Kalvakolanu DV. A proteomic analysis reveals lower in hepatocellular carcinoma patients with the loss of expression of the cell death regulatory gene deteriorating differentiation states, hepatic capsule GRIM-19 in human renal cell carcinomas. Oncogene. 2006 invasion and microvascular invasion (Hao et al., Nov 16;25(54):7138-47 2012). Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Gliomas Kalvakolanu DV. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and Gliomas express NDUFA13 at low levels and this retinoic acid combination, using a genetic approach. J Biol plays a major role in tumorigenesis of the brain. Chem. 2000 Oct 27;275(43):33416-26 NDUFA13 mRNA and protein levels are Barnich N, Hisamatsu T, Aguirre JE, Xavier R, Reinecker significantly lower in gliomas than in control brain HC, Podolsky DK. GRIM-19 interacts with nucleotide tissues. NDUFA13 expression levels negatively oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells. correlates with malignancy of the gliomas (Zhang et J Biol Chem. 2005 May 13;280(19):19021-6 al., 2011). Chao L, Wang X, Yang Y, Cui W, Xu J, Chen H, Hao A, Cervical cancer Deng X. Downregulation of gene expression and activity of GRIM-19 affects mouse oocyte viability, maturation, embryo Zhou et al. have shown that reduction of the levels development and implantation. J Assist Reprod Genet. of NDUFA13 protein occurs in primary cervical 2015 Mar;32(3):461-70

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 435

NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13) Pinto M, Máximo V.

Chen H, Wu Q. Expression of GW112 and GRIM-19 in ML. Gene associated with retinoid-interferon-induced colorectal cancer tissues. J BUON. 2015 Mar- mortality 19 attenuates murine autoimmune arthritis by Apr;20(2):438-42 regulation of th17 and treg cells Arthritis Rheumatol 2014 Mar;66(3):569-78 Chidambaram NV, Angell JE, Ling W, Hofmann ER, Kalvakolanu DV. Chromosomal localization of human Nallar SC, Kalakonda S, Lindner DJ, Lorenz RR, Lamarre GRIM-19, a novel IFN-beta and retinoic acid-activated E, Weihua X, Kalvakolanu DV. Tumor-derived mutations in regulator of cell death. J Interferon Cytokine Res. 2000 the gene associated with retinoid interferon-induced Jul;20(7):661-5 mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote Cui WJ, Chao L, Deng XH, Shen YJ, Yang F, Feng WJ, Xu oncogenesis J Biol Chem 2013 Mar 15;288(11):7930-41 J, Chen HL. Expression of gene associated with retinoid- interferon-induced mortality-19 in preimplantation embryo of Seo T, Lee D, Shim YS, Angell JE, Chidambaram NV, mice. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2012 Kalvakolanu DV, Choe J. Viral interferon regulatory factor 1 Jun;34(3):212-5 of Kaposi's sarcoma-associated herpesvirus interacts with a cell death regulator, GRIM19, and inhibits Donatini G, Beaulieu A, Castagnet M, Kraimps JL, Levillain interferon/retinoic acid-induced cell death J Virol 2002 P, Fromont G. Thyroid Hürthle cell tumors: research of Sep;76(17):8797-807 potential markers of malignancy. J Endocrinol Invest. 2016 Feb;39(2):153-8 Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, Poli V, Stark GR, Kalvakolanu DV. The cell death regulator Fan XY, Jiang ZF, Cai L, Liu RY. Expression and clinical GRIM-19 is an inhibitor of signal transducer and activator of significance of GRIM-19 in lung cancer. Med Oncol. 2012 transcription 3 Proc Natl Acad Sci U S A 2003 Aug Dec;29(5):3183-9 5;100(16):9342-7 Hao H, Liu J, Liu G, Guan D, Yang Y, Zhang X, Cao X, Liu Zhang XY, Li M, Sun K, Chen XJ, Meng J, Wu L, Zhang P, Q. Depletion of GRIM-19 accelerates hepatocellular Tong X, Jiang WW. Decreased expression of GRIM-19 by carcinoma invasion via inducing EMT and loss of contact DNA hypermethylation promotes aerobic glycolysis and cell inhibition. J Cell Physiol. 2012 Mar;227(3):1212-9 proliferation in head and neck squamous cell carcinoma Hao M, Shu Z, Sun H, Sun R, Wang Y, Liu T, Ji D, Cong X. Oncotarget 2015 Jan 1;6(1):101-15 GRIM-19 expression is a potent prognostic marker in Zhang Y, Hao H, Zhao S, Liu Q, Yuan Q, Ni S, Wang F, Liu colorectal cancer. Hum Pathol. 2015 Dec;46(12):1815-20 S, Wang L, Hao A. Downregulation of GRIM-19 promotes Huang G, Lu H, Hao A, Ng DC, Ponniah S, Guo K, Lufei C, growth and migration of human glioma cells Cancer Sci Zeng Q, Cao X. GRIM-19, a cell death regulatory protein, is 2011 Nov;102(11):1991-9 essential for assembly and function of mitochondrial Zhou T, Chao L, Rong G, Wang C, Ma R, Wang X. Down- complex I Mol Cell Biol 2004 Oct;24(19):8447-56 regulation of GRIM-19 is associated with STAT3 Huang Y, Yang M, Yang H, Zeng Z. Upregulation of the overexpression in breast carcinomas Hum Pathol 2013 GRIM-19 gene suppresses invasion and metastasis of Sep;44(9):1773-9 human gastric cancer SGC-7901 cell line Exp Cell Res Zhou Y, Li M, Wei Y, Feng D, Peng C, Weng H, Ma Y, Bao 2010 Aug 1;316(13):2061-70 L, Nallar S, Kalakonda S, Xiao W, Kalvakolanu DV, Ling B. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong Down-regulation of GRIM-19 expression is associated with CT, Cao X. GRIM-19, a death-regulatory gene product, hyperactivation of STAT3-induced gene expression and suppresses Stat3 activity via functional interaction EMBO J tumor growth in human cervical cancers J Interferon 2003 Mar 17;22(6):1325-35 Cytokine Res 2009 Oct;29(10):695-703

Máximo V, Lima J, Soares P, Silva A, Bento I, Sobrinho- This article should be referenced as such: Simõ M. GRIM-19 in Health and Disease Adv Anat Pathol 2008 Jan;15(1):46-53 Pinto M, Máximo V. NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13). Atlas Genet Cytogenet Moon YM, Lee J, Lee SY, Her YM, Ryu JG, Kim EK, Son Oncol Haematol. 2016; 20(8):431-436. HJ, Kwok SK, Ju JH, Yang CW, Park SH, Kim HY, Cho

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(8) 436