ATPAF2 (ATP synthase mitochondrial F1 complex assembly factor 2) is a nuclear-encoded mitochondrial chaperone protein essential for assembling the F1 sector of the F1Fo-ATP synthase complex 1. As the mammalian homolog of yeast Atp12p, ATPAF2 facilitates the assembly of alpha and beta subunits into functional ATP synthase 2. Unlike the constitutively expressed ATPAF1, ATPAF2 shows tissue-specific expression patterns, with particularly high levels in brown adipose tissue, correlating with F1-ATP synthase subunit expression across tissues 2. ATPA2 deficiency results in severe mitochondrial dysfunction. Atpaf2-knockout mice are embryonically lethal, contrasting with viable but compromised Atpaf1-deficient mice 1. Loss of ATPAF2 leads to decreased F1 content and ATP synthase dimers, accompanied by ultrastructural mitochondrial abnormalities including cristae loss and impaired oxidative phosphorylation capacity 1. ATPAF2 mutations cause mitochondrial complex V deficiency, presenting as early-onset encephalocardiomyopathies with neonatal lactic acidosis, 3-methylglutaconic aciduria, and multi-organ failure [PMID:24564666; 38]. Recent structural studies reveal ATPAF2 forms functionally relevant protein-protein interactions with other assembly factors 4. Additionally, ATPAF2 loss acts as a genetic sensitizer to pro-apoptotic mitochondrial stress 5.