2.8.2. NDUFB6

The NDUFB6 gene is located on chromosome 9. NDUFB6 is a single-pass membrane protein with its N-terminus found on the matrix side. It is a 15 kDa protein with 127 amino acids, with residues 6–26 forming an alpha helix on the matrix side and residues 56–92 forming an alpha-helix that crosses the membrane. Its initiator methionine is removed during processing. Furthermore, it contains an N-acetylated threonine at residue 2 [58] and a N6-acetylated lysine at residue 24 by analogy with mouse [82]. NDUFB6 contacts NDUFB5, NDUFAB1, and NDUFB9 on the matrix side, core subunit ND5 in the membrane, and supernumerary subunits NDUFB7 and NDUFB10 in the IMS. In a knockout strain of cultured human cells, the loss of NDUFB6 resulted in no assembly of complex I [11].

It has been established that insulin-resistance and type 2 diabetes are associated with reduced NDUFB6 expression [83]. To date, only one polymorphism has been found in NDUFB6 [84]. This polymorphism, rs629566 (A/G or G/G), is located in the promoter region of the NDUFB6 gene. It changes the DNA sequence at position 544 from CA to CG. This polymorphism introduces a fourth potential methylation site in the promoter of the NDUFB6 gene. The introduction of a fourth methylation site resulted in increased DNA methylation at the NDUFB6 gene promoter and decreased NDUFB6 mRNA expression in the muscle of elderly patients. As predicted, elderly patients with the rs629566 G/G genotype had lower NDUFB6 mRNA expression than elderly patients with the A/G genotype. Surprisingly, young patients with the A/G polymorphism had the same level of NDUFB6 mRNA expression as young patients with the wild-type A/A gene. Moreover, young patients with the G/G genotype actually had the highest levels of NDUFB6 mRNA. Thus, it was concluded that age significantly affects NDUFB6 DNA methylation and influences NDUFB6 expression.

Furthermore, it has been suggested that NDUFB6 is a possible tumor suppressor of metastatic clear cell renal cell carcinoma (ccRNC) [85]. In an analysis of 50 primary ccRNC samples, copy number alteration at the 9p24.3–p13.3 region (the chromosomal region in which NDUFB6 gene is located) was found to strongly correlated with poor ccRNC prognosis. Patients missing this chromosomal region had higher cancer recurrence rates, higher metastasis rates, and lower survival rates. It was determined that NDUFB6 expression was downregulated in primary ccRNC samples due to gene copy number loss. More focused experimentation revealed that when NDUFB6-encoded lentiviruses were transduced into a ccRNC cell line, cell proliferation was suppressed. Consequently, it was observed that siRNA knockdown of NDUFB6 led to cell proliferation with the same cell line. The study concluded that loss of region 9p24.1–p13.3 results in NDUFB6 downregulation, which causes cell proliferation in metastatic ccRNC tumors.
