NDUFS8 encodes a core subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), essential for electron transfer from NADH to ubiquinone and ATP synthesis 1. As an iron-sulfur cluster-containing protein, NDUFS8 is critical for both catalytic activity and assembly of Complex I 2. The gene is regulated by transcription factors YY1 and Sp1, with ubiquitous expression predominating in heart and skeletal muscle 3. NDUFS8 dysfunction has multiple disease implications. Pathogenic variants cause infantile-onset mitochondrial disorders including Leigh syndrome 2, with mutations frequently mapping to subunit interfaces disrupting Complex I assembly 4. Recent evidence reveals NDUFS8's critical role in endothelial cell angiogenesis through Akt-mTOR pathway activation; NDUFS8 depletion impairs proliferation, migration, and capillary formation by reducing ATP production and increasing oxidative stress 5. Elevated NDUFS8 expression occurs in proliferative diabetic retinopathy tissues. Additionally, genome-wide association studies identify NDUFS8 as an Alzheimer's disease-causal mitochondrial dysfunction gene, regulated by DNA methylation and interacting with inflammatory cytokines 6. MSC-mediated repair of age-related atrophic gastritis involves NDUFS8-dependent mitochondrial autophagy restoration 7. NDUFS8 assembly depends on the assembly factor NDUFAF6 8, highlighting therapeutic targeting potential for mitochondrial diseases.