ATP5F1E encodes the epsilon subunit of mitochondrial ATP synthase (Complex V), a critical component of the F1 catalytic domain that produces ATP from ADP using the proton gradient generated by the electron transport chain 1. The ATP synthase complex consists of a soluble F1 head domain and a membrane F0 domain linked by a central stalk that rotates during catalysis, coupling ATP synthesis to proton translocation 1. ATP5F1E plays an essential role in F1 assembly and may be important for incorporating the hydrophobic subunit c into the F0 rotor 2. Biallelic and de novo mutations in ATP5F1E cause mitochondrial complex V deficiency with highly variable neurologic phenotypes 3. Three unrelated patients shared an identical homozygous missense ATP5F1E mutation associated with significantly reduced ATP synthase amounts and defective assembly 3. Clinical presentations ranged from hypotonia with spontaneous resolution to severe epilepsy with early death, commonly including movement disorders, developmental delay, intellectual disability, and hyperlactatemia 3. Beyond classical mitochondrial disease, ATP5F1E dysfunction has emerged in autoimmune kidney disease pathogenesis, where reduced expression correlates with mitochondrial dysfunction and tubular damage 4. In colorectal cancer, ATP5F1E marks a glycolytic tumor-associated macrophage subtype enriched in primary tumors and lymph nodes, contributing to immunosuppression 5.