NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial

NDUFS3 is a core iron-sulfur subunit of mitochondrial respiratory chain Complex I (NADH dehydrogenase), essential for catalyzing electron transfer from NADH through ubiquinone and for the catalytic activity and assembly of the complex (UniProt: O75489). The protein is expressed in mitochondria across tissues and is functionally central to oxidative phosphorylation.

Pathogenic variants in NDUFS3 cause mitochondrial complex I deficiency, nuclear type 8 (MC1DN8; MIM 618230), an autosomal recessive mitochondrial disorder characterized by defective energy metabolism. Clinical presentations range from lethal neonatal disease to adult-onset neurodegenerative phenotypes including progressive leukodystrophy, encephalopathy, cardiomyopathy, and Parkinson-like features (UniProt: O75489).

In Alzheimer's disease, NDUFS3 shows increased abundance in post-mortem AD brain relative to age-matched controls (mean log2 fold-change: 1.53; Chaparral AD proteomics). The upregulation suggests potential compensatory responses or mitochondrial dysfunction associated with AD pathogenesis, though the functional significance in AD progression requires further investigation.