ATP5PO encodes the oligomycin sensitivity-conferring protein (OSCP), a critical peripheral stalk subunit of mitochondrial ATP synthase (Complex V) 1. This protein stabilizes the peripheral stalk that links the catalytic F1 head domain to the membrane F0 domain, acting as a stator to maintain proper positioning of the catalytic core during ATP synthesis coupled to proton translocation 2. ATP5PO also functions as a key regulator of the mitochondrial permeability transition pore (mPTP) 3. Biallelic variants in ATP5PO cause severe mitochondrial complex V deficiency, manifesting as infantile-onset Leigh syndrome characterized by hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epilepsy, cerebral atrophy, and often early lethality 14. A homozygous splice variant (c.87+3A>G) produces a non-functional protein lacking exon 2, leading to reduced ATP5PO protein levels, defective complex V assembly, and markedly reduced oxidative phosphorylation 1. Heterozygous de novo mutations also cause variable neurologic phenotypes including dystonia and developmental delay 5. ATP5PO overexpression paradoxically reduces ATP5PO protein levels and impairs ENS development, linking ATP5PO dosage balance to Hirschsprung disease risk in Down Syndrome patients 6. Additionally, ATP5PO glutathionylation regulates mPTP function and represents a therapeutic vulnerability in acute myeloid leukemia 3.