2.4.2. NDUFB9

The gene for NDUFB9 is located on chromosome 8. It is encoded as a protein of 179 amino acids, with a mass of about 21.8 kDa. The N-terminal Met is likely removed, and other possible modifications include the acetylation of Ala2 [58] and the phosphorylation of Ser85 [59]. NDUFB9 is a peripheral protein that is bound to the matrix side of core subunit ND5, with significant contacts to NDUFAB1, one of the acyl carrier proteins (see Figure 9b), and to NDUFB3, NDUFB4, NDUFB5, and NDUFB6. The protein is U-shaped, with each arm consisting of a three-helix bundle and pointing away from ND5. NDUFB9, along with NDUFA6, is a member of the LYR protein family, characterized by a Leu–Tyr–Arg motif near the N-terminus. In the case of NDUFB9, the motif is Leu19–Tyr20–Lys21, and it is found in the N-terminal alpha-helix. The acyl carrier protein NDUFAB1 fits between the two helical domains and binds to Tyr20 and Lys21 of this motif. In a cell line in which NDUFB9 was knocked out, complex I failed to assemble [11].

In 2012, a large-scale mutation-screening identified two patients who carried NDUFB9 mutations [60]. One patient, who presented withlactic acidemia andmuscular hypotonia, was homozygous for the missense p.Leu64Pro. This residue is found in the third helix and packs against the first helix in the N-terminal three-helix bundle. Complex I activity was about 39% of the normal activity. After lentiviral rescue with a wild-type NDUFB9 gene, both complex I activity and levels of other complex I subunits were restored to normal levels. A second individual was found to carry the heterozygous mutation Arg47Leu, but this mutation was not found in a sibling with similar symptoms and could not be rescued by the complementation with a wild-type NDUFB9 gene. Therefore, it was concluded that illness was due to another gene.
