APOO (apolipoprotein O) serves as a crucial component of the mitochondrial MICOS complex, playing essential roles in mitochondrial cristae junction formation and inner membrane architecture 12. The protein functions both intracellularly as a mitochondrial component and extracellularly in lipid metabolism. Within mitochondria, APOO localizes to the inner membrane where it maintains cristae morphology and promotes mitochondrial respiration and fatty acid metabolism 3. Loss-of-function mutations in APOO cause severe mitochondrial diseases characterized by impaired cristae architecture, developmental delay, and neuromuscular dysfunction 24. In lipid metabolism, APOO regulates plasma cholesterol levels through an NRF2/CYB5R3 pathway that controls cholesterol excretion via bile and feces, independent of the LDL receptor 5. The protein also promotes cholesterol efflux from macrophages and is secreted in association with lipoproteins 6. Clinically, APOO expression is elevated in diabetic cardiomyopathy and myocardial infarction, where it contributes to cardiac lipotoxicity and activates autophagy through p38MAPK signaling 37. Pathogenic variants cause lethal mitochondrial disorders with progeria-like features, highlighting APOO's critical role in cellular energy metabolism and disease pathogenesis.