An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix

The physiological function of the human uncoupling protein 3 UCP3, which wa s discovered in 1997, is unknown. Here we evaluate the available data on hu man UCP3 expression and show that UCP3 is up-regulated in situations where fatty acid delivery to the mitochondria exceeds oxidative capacity, whereas down-regulation of UCP3 is observed when oxidative capacity is enhanced. W ith a surplus of fatty acid delivery, accumulation of nonesterified fatty a cids in the cytoplasm is likely to occur. Although the inner mitochondrial membrane provides a barrier for nonesterified fatty acids, neutral nonester ified fatty acids can partition into the phospholipid bilayer and flip-flop to the other side of the membrane, where they can be released into the mit ochondrial matrix. Due to pH differences, these nonesterified fatty acids w ill be protonated. Because fatty acid anions can neither be metabolized ins ide the matrix or cross the inner mitochondrial membrane, accumulation of n onesterified fatty acids inside the matrix might occur. Therefore, we postu late that UCP3 is required for the outward translocation of fatty acids fro m the mitochondrial matrix. In this way, UCP3 is involved in the protection of mitochondria against accumulation of nonesterified fatty acids inside t he mitochondrial matrix.