Structural Bias in Vitamin A Metabolism: Why α-Retinoids Miss the Eye

Provitamin A carotenoids are metabolized to retinoids, critical for vision and transcriptional regulation, through oxidative cleavage by carotenoid oxygenases. β-Carotene, a symmetric carotenoid, undergoes central cleavage by β-carotene oxygenase 1 (BCO1), generating two molecules of retinaldehyde. In contrast, the metabolism of asymmetric carotenoids, such as α-carotene (β,ε-carotene) and β-cryptoxanthin (β,β-carotene-3-ol), produces noncanonical apocarotenoid derivatives in addition to retinaldehyde. Here, we dissect the enzymatic pathways and transport mechanisms governing these metabolic fates in mice. We demonstrate that α-carotene is cleaved exclusively by BCO1 to yield retinaldehyde and α-retinaldehyde, bypassing mitochondrial processing. β-Cryptoxanthin, however, undergoes an initial eccentric cleavage by mitochondrial BCO2, followed by cytosolic BCO1-mediated central cleavage, producing only retinaldehyde. This divergence arises from differential subcellular trafficking: β-cryptoxanthin is transported to mitochondria via Aster-B, while α-carotene is excluded. Downstream, α-retinol is esterified by lecithin:retinol acyltransferase (LRAT), trafficked in chylomicrons, and stored as α-retinyl esters in the liver under ISX-mediated transcriptional control. Notably, α-retinol is not mobilized into circulation via retinol binding protein 4 (RBP4), and, genetic ablation of its receptor, STRA6 does not alter α-retinyl ester storage in lung tissue. Intriguingly, α-retinyl esters accumulate in the eyes of STRA6-deficient mice yet fail to participate in the visual cycle due to exclusion from RPE65-mediated isomerization. These findings establish α-retinoids as metabolic tracers of BCO1 activity and chylomicron-mediated vitamin A delivery and reveal mechanistic safeguards that prevent incorporation of noncanonical retinoids into the visual cycle.