Abstract
The mitochondrial membrane uncoupling protein UCP3 belongs to the SLC25 solute carrier family and transports protons across the inner mitochondrial membrane. Based on the knowledge that another uncoupling protein - UCP2 - transports C4 metabolites (malate, oxaloacetate, and aspartate)1 and there is high homology between UCP2 and UCP3, we hypothesized that UCP3 also transports these metabolites. To test this, we measured the transport of C4 metabolites against phosphate (32Pi) in proteoliposomes reconstituted with recombinant murine UCP3. We found that UCP3 transports primarily aspartate and sulfate, but also malate, malonate, oxaloacetate, and succinate. The transport rates from the exchange of 32Pi for extraliposomal aspartate and sulfate were 0.89 ± 0.33 and 0.61 ± 0.12 µmol/min/mg, respectively. We demonstrated that UCP3 preferentially transports malate, oxaloacetate, and aspartate against phosphate plus a proton from opposite side of the membrane, which does not exactly match the transport pattern of UCP2. Because UCP3 and UCP2 are expressed in different tissues2, we anticipate that their substrate specificity may differ. The putative physiological role of UCP3-mediated substrate transport in cells dependent on fatty acid oxidation is discussed. 1. Vozza A, et al. UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proc. Natl. Acad. Sci. U S A 111, 960-965 (2014). 2. Pohl EE, Rupprecht A, Macher G, Hilse KE. Important Trends in UCP3 Investigation. Front Physiol. 10, 470 (2019).
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