Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFAF7
Cytogenetic location: 2p22.2 Genomic coordinates (GRCh38): 2:37,231,658-37,271,365 (from NCBI)
N-methylation of proteins involves the enzymatic addition of methyl groups donated by S-adenosylmethionine (SAM) to the side-chain nitrogen atoms of lysine and arginine, the imidazole side chain of histidine, or the alpha-N atom of the protein. NDUFAF7 transiently interacts with and dimethylates an arginine of NDUFS2 (602985), a core subunit of mitochondrial complex I. This dimethylation stabilizes an early subcomplex that nucleates an arm of mature complex I (summary by Rhein et al., 2013).
By searching databases for proteins similar to Dictyostelium MidA, Carilla-Latorre et al. (2010) identified human NDUFAF7, which they called MIDA. They identified orthologs in a wide array of species, but not in yeast, which do not have mitochondrial complex I. The deduced Dictyostelium and human proteins have an N-terminal mitochondrial localization signal followed by a SAM-dependent methyltransferase domain. Fluorescence-tagged MIDA localized to mitochondria in transfected HeLa and HEK293T cells. Native gel electrophoresis revealed that fluorescence-tagged MIDA formed homodimers.
Zurita Rendon et al. (2014) identified 13 predicted NDUFAF7 splice variants, only 2 of which were predicted to be translated. The full-length 441-amino acid NDUFAF7 protein has a calculated molecular mass of 49 kD. It has a predicted mitochondrial targeting signal and a central SAM-dependent methyltransferase domain with a characteristic glycine-rich motif I. The smaller NFUFAF7 isoform, which as a calculated molecular mass of 38 kD, was predicted to lack sequences on both sides of motif I. RT-PCR analysis of human fibroblasts detected NDUFAF7 transcripts of 1.3 and 1.0 kb. Immunofluorescence analysis, subcellular fractionation, and differential extraction experiments revealed that NDUFAF7 localized to the mitochondrial compartment and behaved as a peripherally associated mitochondrial protein. Full-length NDUFAF7 had an apparent molecular mass of approximately 50 kD by 2-dimensional SDS-PAGE.
Zurita Rendon et al. (2014) determined that the NDUFAF7 gene has 10 exons.
Hartz (2014) mapped the NDUFAF7 gene to chromosome 2p22.2 based on an alignment of the NDUFAF7 sequence (GenBank BC004548) with the genomic sequence (GRCh37).
Using short hairpin RNA, Carilla-Latorre et al. (2010) found that knockdown of MIDA reduced complex I assembly and activity in HEK293T cells. Protein pull-down and immunoprecipitation experiments revealed that both Dictyostelium and human MIDA bound NDUFS2, suggesting a conserved role for MIDA in complex I assembly.
Rhein et al. (2013) found that knockdown of NDUFAF7 in human osteosarcoma cells reduced the rate of oxygen consumption by complex I and, later, by complex III. NDUFAF7 symmetrically dimethylated the guanidino group of arg85 (R85) in NDUFS2, and knockdown of NDUFAF7 progressively shifted the methylation status of R85 from dimethylated to nonmethylated, concomitant with loss of complex I assembly.
Zurita Rendon et al. (2014) found that small interfering RNA-mediated knockdown of NDUFAF7 in human fibroblasts depleted fully assembled complex I, but did not affect other mitochondrial complexes. Immunoprecipitation analysis revealed that NDUFAF7 associated with a mitochondrial subcomplex that contained ND1 (MTND1; 516000). Knockdown of NDUFAF7 reduced the content of ND1, which was rescued by inhibition of the mitochondrial inner membrane protease AFG3L2 (604581). Knockdown of NDUFAF7 also caused depletion of NDUFS2 and NDUFA9 (603834). Mutation of the first glycine (gly124) in the GxGxG methyltransferase motif I of NDUFAF7 also reduced the steady-state levels of ND1, NDUFS2, and NDUFA9 and reduced dimethylation of NDUFS2 on R85. Zurita Rendon et al. (2014) concluded that the methyltransferase activity of NDUFAF7 is required for its function in complex I assembly.
Wang et al. (2017) reported a 55-year-old woman of Han Chinese descent with pathologic myopia associated with a heterozygous missense variant in the NDUFAF7 gene (c.798C-G; D266E). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was also present in her similarly affected mother and daughter. The proband had progressive age-related bilateral visual loss. Funduscopy showed prominent posterior staphyloma, tessellation, attenuated retinal vessel, patchy atrophy, and peripapillary atrophy, and optical coherence tomography showed reduced retinal fiber thickness. In vitro functional expression studies in cells transfected with the variant showed decreased ATP and ROS production and a mild reduction in mitochondrial complex I activity (reduced by 9% compared to controls). Whole-exome sequencing also identified variants in 7 different genes that segregated with the disorder in the family: these included GLTPD1 (615467), C2ORF71 (613425), RHO (180380), and ZBTB38 (612218), which the authors could not exclude from contributing to the phenotype.
Zurita Rendon et al. (2014) found that knockout of Ndufaf7 in mice was embryonic lethal. Ndufaf7 -/- embryos were recovered at the blastocyst stage, but not at embryonic day 10.5. Morpholino-mediated knockdown of ndufaf7 in zebrafish delayed hatching, caused morphologic abnormalities, and reduced steady-state levels of mitochondrial complex I.
Carilla-Latorre, S., Gallardo, M. E., Annesley, S. J., Calvo-Garrido, J., Grana, O., Accari, S. L., Smith, P. K., Valencia, A., Garesse, R., Fisher, P. R., Escalante, R. MidA is a putative methyltransferase that is required for mitochondrial complex I function. J. Cell Sci. 123: 1674-1683, 2010. [PubMed: 20406883] [Full Text: https://doi.org/10.1242/jcs.066076]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/22/2014.
Rhein, V. F., Carroll, J., Ding, S., Fearnley, I. M., Walker, J. E. NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of human complex I. J. Biol. Chem. 288: 33016-33026, 2013. [PubMed: 24089531] [Full Text: https://doi.org/10.1074/jbc.M113.518803]
Wang, B., Liu, Y., Chen, S., Wu, Y., Lin, S., Duan, Y., Zheng, K., Zhang, L., Gu, X., Hong, W., Shao, H., Zeng, X., Sun, B., Duan, S. A novel potentially causative variant of NDUFAF7 revealed by mutation screening in a Chinese family with pathologic myopia. Invest. Ophthal. Vis. Sci. 58: 4182-4192, 2017. [PubMed: 28837730] [Full Text: https://doi.org/10.1167/iovs.16-20941]
Zurita Rendon, O. Z., Silva Neiva, L., Sasarman, F., Shoubridge, E. A. The arginine methyltransferase NDUFAF7 is essential for complex I assembly and early vertebrate embryogenesis. Hum. Molec. Genet. 23: 5159-5170, 2014. [PubMed: 24838397] [Full Text: https://doi.org/10.1093/hmg/ddu239]