Disruption of carotenoid metabolism in cavefish via loss of beta-carotene oxygenase 2a.

Vitamin A is an essential micronutrient that supports vision, immunity, and development, yet excess vitamin A can be toxic. Most vertebrates maintain tightly regulated vitamin A levels by cleaving dietary carotenoids into retinoids via specialized enzymes, including the carotenoid oxygenase Bco2. To what extent genetic changes in carotenoid-metabolism enzymes such as Bco2 drive natural variation in vitamin A homeostasis remains unclear. Here, we show that some cave-adapted populations of the Mexican tetra (Astyanax mexicanus) have evolved loss-of-function mutations in bco2a. The mutations yield enzymatically inactive Bco2a proteins and are associated with dramatic carotenoid and vitamin A accumulation. The bco2a locus shows signatures of selection in these cavefish populations, suggesting that loss of Bco2a function could be advantageous under certain cave conditions. Contrary to expectations from mammalian models in which Bco2 loss induces oxidative damage, cavefish appear to tolerate carotenoid accumulation and may benefit from elevated carotenoid stores in nutrient-variable caves. Our findings reveal that the vitamin A regulatory system is evolutionarily flexible and provide a framework for understanding how animals balance essential nutrient thresholds in extreme environments. VIDEO ABSTRACT.