Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation

Multiple myeloma is a plasma cell malignancy that develops within the bone marrow. The bone marrow metabolome is altered in myeloma, with implications for malignant cell growth. Here, the impact of elevated bone marrow levels of the tricarboxylic acid (TCA) cycle metabolite, succinate, was interrogated. Succinate was found to promote proliferation of several myeloma cell lines. This was linked to its uptake and oxidation in the TCA cycle, as indicated by increased ATP-coupled mitochondrial respiration and incorporation of succinate-derived carbons into downstream TCA cycle intermediates, which also occurs in primary myeloma cells. Succinate-driven proliferation was dependent upon mitochondrial oxidative phosphorylation and abrogated by ATP synthase inhibition. Furthermore, interrogation of large-scale transcriptomic data identified that elevated expression of a mitochondrial succinate transporter associates with accelerated disease progression in myeloma, indicating this mechanism may promote plasma cell growth in vivo and highlighting a target for therapeutic intervention.