Evidence for compartmentalization of mammalian carotenoid metabolism

The critical role of retinoids (vitamin A and its derivatives) for vision, reproduction, and survival has been well established. Vitamin A is produced from dietary carotenoids such as β‐carotene by centric cleavage via the enzyme BCO1. The biochemical and molecular identification of a second structurally related β‐carotene metabolizing enzyme, BCO2, has led to a prolonged debate about its relevance in vitamin A biology. While BCO1 cleaves provitamin A carotenoids, BCO2 is more promiscuous and also metabolizes non‐provitamin A carotenoids such as zeaxanthin into long‐chain apo‐carotenoids. Herein we demonstrate, in cell lines, that human BCO2 is associated with the inner mitochondrial membrane. Different human BCO2 isoforms possess cleavable N‐terminal leader sequences critical for mitochondrial import. Subfractionation of murine hepatic mitochondria confirmed the localization of BCO2 to the inner mitochondrial membrane. Studies in BCO2‐knockout mice revealed that zeaxanthin accumulates in the inner mitochondrial membrane; in contrast, β‐carotene is retained predominantly in the cytoplasm. Thus, we provide evidence for a compartmentalization of carotenoid metabolism that prevents competition between BCO1 and BCO2 for the provitamin and the production of noncanonical β‐carotene metabolites.—Palczewski, G., Amengual, J., Hoppel, C. L., von Lintig, J., Evidence for compartmentalization of mammalian carotenoid metabolism. FASEB J. 28, 4457–4469 (2014). www.fasebj.org