NDUFS5 is an accessory subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), which catalyzes electron transfer from NADH to ubiquinone in the respiratory chain 1. As a structural component rather than catalytic subunit, NDUFS5 is essential for Complex I assembly and function 2. The protein is ubiquitously expressed across human tissues, with elevated expression in metabolically active organs including heart, skeletal muscle, and liver 1. NDUFS5 import into mitochondria depends on the AIFM1-MIA40/CHCHD4 disulfide relay system; disruption of this pathway causes cytosolic NDUFS5 accumulation, proteasomal degradation, and Complex I assembly failure 2. NDUFS5 dysfunction has been linked to multiple disease states. In Alzheimer's disease, NDUFS5 shows significantly reduced expression in affected individuals and serves as a diagnostic biomarker when combined with other mitochondrial genes 34. Dysregulated NDUFS5 expression has also been identified in glioma and may contribute to tumorigenesis 5. In non-ischemic cardiomyopathy, reduced NDUFS5 expression correlates with improved left ventricular reverse remodeling, suggesting compensatory metabolic adaptation 6. Additionally, NDUFS5 methylation patterns are associated with psychosocial stress and may influence gene expression 7. These associations implicate mitochondrial respiratory dysfunction in neurodegenerative, neoplastic, and cardiovascular pathologies.