Speaker
Description
Cellular metabolism can be viewed as a compartmental reaction network constrained by stoichiometry, transport processes, and enzymatic capacities. Mitochondrial transporters couple mitochondrial and cytosolic metabolism, yet their impact on feasible flux states remains poorly understood. Mutations in succinate dehydrogenase (SDH), observed in several cancers and mitochondrial disorders, lead to accumulation of succinate, an oncometabolite, and metabolic rewiring. SLC25A10, the mitochondrial dicarboxylate carrier, catalyses exchange of succinate and malate with phosphate and other inorganic anions across the inner mitochondrial membrane. Here, we analyse how transport perturbations reshape flux distributions. We combine stable-isotope labelling experiments ($^{13}$C-glucose) with constraint-based metabolic modelling to infer condition-specific flux states in wild-type, SDH-deficient, SLC25A10-deficient, and combined SDH/SLC25A10-deficient cells. In SDH-competent cells, SLC25A10 sustains mitochondrial-cytosolic malate exchange and supports anaplerotic coupling of the tricarboxylic acid cycle. Under SDH deficiency, isotope-consistent model solutions suggest that SLC25A10 contributes to succinate export, while its loss requires compensatory flux through alternative carriers, with SLC25A1 emerging as a plausible route. These results show how transport processes shape feasible flux states and enable metabolic plasticity under mitochondrial dysfunction. This reveals hidden rewiring.
