NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial

NDUFS6 is an accessory subunit of mitochondrial Complex I (NADH dehydrogenase), a key enzyme complex involved in the transfer of electrons from NADH to the respiratory chain during oxidative phosphorylation (UniProt: O75380). The protein is not believed to directly participate in catalysis but functions as a structural component supporting Complex I assembly and function in the inner mitochondrial membrane.

NDUFS6 is expressed in mitochondria-rich tissues and is associated with mitochondrial complex I deficiency when mutated. Pathogenic variants cause MC1DN9 (mitochondrial complex I deficiency, nuclear type 9; MIM 618232), an autosomal recessive disorder characterized by defective oxidative phosphorylation and variable clinical manifestations including progressive neurodegeneration, Leigh syndrome, and some forms of Parkinson disease (UniProt: O75380).

In Alzheimer's disease, NDUFS6 shows elevated abundance in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of 1.05 (Chaparral AD proteomics). This upregulation was detected via TMT-labeled quantitative proteomics across subcellular fractions, suggesting potential involvement of mitochondrial dysfunction in AD pathogenesis, though the functional significance requires further investigation.