NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial

NDUFS2 (NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial) is a core subunit of mitochondrial Complex I that catalyzes electron transfer from NADH through the respiratory chain via ubiquinone. The protein is essential for both the catalytic activity and assembly of Complex I and plays a critical role in oxidative phosphorylation (UniProt: O75306). It also functions as a redox-sensitive component of the oxygen-sensing pathway in pulmonary vasculature and supports neural stem and progenitor cell proliferation and differentiation.

Mutations in NDUFS2 are associated with mitochondrial complex I deficiency, nuclear type 6 (MC1DN6), an autosomal recessive disorder presenting with variable severity ranging from lethal neonatal disease to adult-onset neurodegeneration, including Leigh syndrome, cardiomyopathy, and leukodystrophy (UniProt: O75306). The protein is also implicated in Leber-like hereditary optic neuropathy, characterized by selective retinal ganglion cell degeneration.

In Alzheimer's Disease, NDUFS2 is upregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of 1.61 (Chaparral AD proteomics). This elevated expression suggests potential compensatory mitochondrial oxidative stress responses or altered energy metabolism in AD pathology.