NDUFAF6 is a mitochondrial assembly factor essential for complex I biogenesis. It facilitates the incorporation of the NDUFS8 subunit into NADH:ubiquinone oxidoreductase complex I during early assembly stages 1. Loss of NDUFAF6 function results in reduced complex I activity and assembly in patient-derived fibroblasts 2. NDUFAF6 mutations cause mitochondrial complex I deficiency with severe neurological consequences. Biallelic NDUFAF6 mutations are associated with Leigh syndrome presenting as early-onset progressive dystonia with bilateral striatal necrosis and basal ganglia degeneration 2. NDUFAF6 variants also cause Fanconi renotubular syndrome 5, a generalized proximal tubular dysfunction disorder 3. A common NDUFAF6 polymorphism (rs6982393) shows age-dependent associations with Alzheimer's disease risk in elderly populations, with TT genotype carriers aged 60-69 showing increased AD susceptibility, particularly when combined with APOE ε4 4. In cancer biology, NDUFAF6 overexpression promotes breast cancer progression through mitochondrial dysfunction-related mechanisms; knockdown enhances apoptosis and mitophagy via impaired oxidative phosphorylation and increased reactive oxygen species 56. NDUFAF6 represents a critical hub linking mitochondrial energy metabolism to neurodegeneration and cancer pathogenesis.