NDUFV1 encodes a core subunit of mitochondrial respiratory chain Complex I (NADH:ubiquinone oxidoreductase), functioning as part of the enzyme's peripheral arm 1. NDUFV1 contains flavin mononucleotide (FMN) and one iron-sulfur cluster, serving as the initial electron acceptor that facilitates electron transfer from NADH through a chain of iron-sulfur clusters to ubiquinone 1. This electron transfer process is essential for oxidative phosphorylation and ATP synthesis, with NDUFV1 activity directly regulating Complex I function and mitochondrial respiration efficiency 2. Pathogenic NDUFV1 variants cause mitochondrial Complex I deficiency, characterized by neuroregression with leukoencephalopathy and basal ganglia involvement 3. Clinical presentations include hypertonia, ocular abnormalities, feeding difficulties, and seizures, with MRI patterns classified as Leigh syndrome, mitochondrial leukodystrophy, or mixed phenotypes 3. Early treatment with mitochondrial cocktail improves outcomes and reduces mortality 3. Beyond primary mitochondrial disorders, NDUFV1 dysregulation is associated with lupus nephritis through altered lactate metabolism pathways 4, colorectal cancer progression via PHB2-mediated stabilization of Complex I 2, myocardial infarction through impaired mitochondrial ATP synthesis 5, and neurodegenerative diseases where reduced NDUFV1 levels correlate with cognitive decline 6.