Alternative titles; symbols
HGNC Approved Gene Symbol: MT-ND4L
SNOMEDCT: 58610003; ICD10CM: H47.22;
Subunit 4L is 1 of the 7 mitochondrial DNA (mtDNA)-encoded subunits (MTND1, MTND2, MTND3, MTND4, MTND4L, MTND5, MTND6) included among the approximately 41 polypeptides of respiratory Complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) (Shoffner and Wallace, 1995; Arizmendi et al., 1992; Walker et al., 1992; Anderson et al., 1981; Attardi et al., 1986; Chomyn et al. (1985, 1986); Wallace et al., 1986; Oliver and Wallace, 1982; Wallace et al., 1994). Complex I accepts electrons from NADH, transfers them to ubiquinone (coenzyme Q10), and uses the energy released to pump protons out across the mitochondrial inner membrane. Complex I is more fully described under 516000. MTND4L is probably a component of the hydrophobic protein fragment of the complex (Ragan, 1987).
MTND4L is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pairs (nps) 10470 and 10766 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
The MTND4L gene encompasses 285 nps of continuous coding sequence and lacks introns. It is a part of a bicistronic mRNA, occupying the 5-prime end while its companion gene, MTND4, occupies the 3-prime end. This mRNA begins with the AUG methionine codon of MTND4L and ends with a stop codon. The terminal 7 nps of MTND4L overlap with the initiation methionine and the next leucine of MTND4 (Anderson et al., 1981). The bicistronic MTND4L+MTND5 mRNA is transcribed as a part of the polycistronic H-strand transcript, flanked by tRNAArg at the 5-prime end and tRNAHis at the 3-prime end. These tRNAs are cleaved from the transcript freeing transcript 7, the MTND4L+MTND4 mRNA. The mRNA is then polyadenylated completing the MTND4 termination codon (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982; Wallace et al., 1994).
The predicted polypeptide molecular weight is 10.7 kD (Anderson et al., 1981; Wallace et al., 1994). However, the apparent molecular weight upon SDS-polyacrylamide gel electrophoresis (PAGE) using Tris-glycine buffer is 14.5 kD (Wallace et al., 1986; Oliver et al., 1984) whereas for urea-phosphate gels, it is 3.5 kD (Chomyn et al., 1985).
Using a yeast 2-hybrid screen and pull-down assays, Li et al. (2005) found that nonstructural protein-10 (NSP10) of SARS coronavirus interacted with components of cellular mitochondria, including NADH4L and cytochrome oxidase II (MTCO2; 516040). Human cells transfected with NSP10 showed altered NADH-cytochrome activity and depolarization of the inner mitochondrial membrane. Moreover, NSP10 appeared to amplify the cytopathic effect of infection with the coronavirus 229E strain.
Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I: +10536/10413, -10598, +10694; Dde I: -10631, +10746; Hae III: -10689, +10725; Rsa I: +10644, +10656, -10737 (Wallace et al., 1994).
Early on, Warburg (1956) suggested that alterations of oxidative phosphorylation in tumor cells play a causative role in cancerous growth. Interest in the mitochondria with regard to neoplasia has revived, largely because of their role in apoptosis and other aspects of tumor biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generated in this organelle, coupled with a low level of DNA repair. In a colorectal cancer, Polyak et al. (1998) found a 10563T-C transition resulting in a cys32-to-arg amino acid substitution in the MTND4L protein.
Approximately 90% of Leber optic atrophy (LHON; 535000) cases are caused by 3460A (516000.0001), 11778A (516003.0001), or 14484C (516006.0001) mtDNA mutations. These are designated 'primary' mutations because they impart a high risk for LHON expression. The 11778A and 14484C mutations are preferentially associated with mtDNA haplogroup J, 1 of 9 Western Eurasian mtDNA lineages, suggesting a synergistic and deleterious interaction between these LHON mutations and haplogroup J polymorphism(s). Brown et al. (2002) reported a novel primary LHON mutation in the ND4L gene. A homoplasmic T-to-C transition at nucleotide 10663 was found in 3 independent LHON patients who lacked a known primary mutation and all of whom belonged to haplogroup J. Phylogenetic analysis with primarily complete mtDNA sequence data demonstrated that the 10663C mutation had arisen at least 3 independent times in haplogroup J, indicating that it is not a rare lineage-specific polymorphism. Analysis of complex I function in patient lymphoblasts and transmitochondrial cybrids revealed a partial complex I defect similar in magnitude to the 14484C mutation. Brown et al. (2002) concluded that 10663C is a primary LHON mutation that is pathogenic when cooccurring with haplogroup J. The results supported a role for haplogroup J in the expression of certain LHON mutations.
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