Human mitochondrial uncoupling protein 3 functions as a metabolite transporter

We show that recombinant human uncoupling protein 3 (UCP3), refolded and reconstituted into liposomes, efficiently transports aspartate and malate, and, to a lesser extent, phosphate and sulphate. Unlike UCP2, UCP3 cannot catalyse unidirectional substrate transport and exhibits an approximately sevenfold higher transport affinity for aspartate compared to UCP2. The R282Q mutation in the sixth α-helix completely abolishes the transport activity of UCP3. Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient “uncoupled” respiration, including fasting and exercise. Here we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, oxaloacetate, and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.

Source: FEBS Letters - December 6, 2023 Category: Biochemistry Authors: Francesco De Leonardis, Amer Ahmed, Angelo Vozza, Loredana Capobianco, Christopher L. Riley, Simona Nicole Barile, Daria Di Molfetta, Stefano Tiziani, John DiGiovanni, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte Tags: Research Letter Source Type: research