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 toxic1,2. Most vertebrates maintain tightly regulated vitamin A levels by cleaving dietary carotenoids into retinoids via specialized enzymes, including the mitochondrial carotenoid oxygenase Bco23,4. 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 damage5,6, 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.