Regulation of Intra- and Intercellular Metabolite Transport in Cancer Metabolism

FabianSpill

University of Birmingham

"Regulation of Intra- and Intercellular Metabolite Transport in Cancer Metabolism"

Metabolite transport is essential for cellular homeostasis, energy production, and metabolic adaptation. In cancer, dysregulated transport sustains tumor growth and alters redox balance. The mitochondrial solute carrier SLC25A10 facilitates succinate, malate, and phosphate exchange, influencing central carbon metabolism. However, its transport kinetics and physiological directionality remain poorly understood. We present a mathematical model of SLC25A10 based on a ping-pong kinetic mechanism, capturing competitive dynamics between malate and succinate. Our simulations reveal that under normal conditions, malate flux dominates due to its higher binding affinity. However, in succinate dehydrogenase (SDH) dysfunction, excess succinate induces a transient efflux shift and phosphate flux reversal. If experimentally validated, this metabolic shift could serve as a biomarker for tumors with SDH mutations. Integrating our kinetic model with genome-scale metabolic networks, we highlight the role of mitochondrial transport in cancer metabolism. Specifically, in multiple myeloma, metabolic crosstalk between plasma cells and bone marrow stromal cells is key to tumor progression. Our findings demonstrate the power of mathematical modeling in uncovering transport-mediated metabolic vulnerabilities, offering potential therapeutic targets for cancer and metabolic diseases.
Additional authors:

---