Adaptive Disruption of Carotenoid Metabolism in Cavefish via Loss of Beta-carotene oxygenase 2a (Bco2a)

Vitamin A is an essential micronutrient that supports vision, immunity, and development, yet excess vitamin A can be toxic ^1,2 . Most vertebrates maintain tightly regulated vitamin A levels by cleaving dietary carotenoids into retinoids via specialized enzymes, including the mitochondrial carotenoid oxygenase Bco2 ^3,4 . To what extent genetic changes in carotenoid-metabolism enzymes like Bco2 drive natural variation in vitamin A homeostasis remains unclear. Here we show that multiple cave-adapted populations of the Mexican tetra ( Astyanax mexicanus ) have evolved loss-of-function mutations in bco2a , leading to impaired carotenoid cleavage and dramatic carotenoid and vitamin A accumulation. These mutations yield enzymatically inactive Bco2a proteins, are under selection in cavefish, and may provide a physiological advantage under inconsistent carotenoid supply. Contrary to expectations from mammalian models where Bco2 loss induces oxidative damage ^5,6 , cavefish appear to tolerate and even benefit from carotenoid accumulation, potentially through enhanced antioxidant capacity and modified mitochondrial metabolism. Our findings reveal that the vitamin A regulatory system is evolutionarily flexible, and that the adaptive loss of Bco2a function may enable survival in nutrient-variable, low-oxygen cave environments. This work provides a framework for understanding how animals balance essential nutrient thresholds in extreme environments.