Mathematical Modelling of the Mitochondrial Dicarboxylate Carrier (SlC25A10)

The mitochondrial dicarboxylate carrier SLC25A10 exchanges phosphate with dicarboxylates such as succinate and malate, playing a central role in metabolic regulation. Structural studies establish a ping–pong mechanism, but most mathematical models still assume sequential binding, lacking mechanistic justification and overlooking the alternation of a single binding site. Here, we present the first mechanistically derived and thermodynamically consistent model of SLC25A10 based on the ping–pong framework. The model incorporates competitive dicarboxylate binding, phosphate exchange, heteroexchange, reversibility, and electroneutrality, and is validated against experimental data. To estimate kinetic parameters and quantify their uncertainty, we employed Bayesian inference, enabling statistically rigorous calibration to competition assays. The model introduces new terms that quantify which substrate and from which side of the membrane is most likely to start the transport cycle. Beyond reproducing rapid exchange of different substrates that cannot be directly measured experimentally, the model captures the influence of mitochondrial morphology, enzymatic interactions, and metabolic perturbations on transporter behavior. Specifically, simulations reveal that swelling of the matrix and intermembrane space dilutes metabolite pools, reduces gradients, and decreases SLC25A10 fluxes. Moreover, the model demonstrates how SLC25A10 contributes to succinate handling under SDH deficiency, functioning both as a gatekeeper and a pressure-release valve for matrix succinate. Under these conditions, succinate accumulates and is exported into the inter-membrane space via SLC25A10, a process critically dependent on phosphate and malate availability.