Succinate Confers Stronger Cytoprotection in Kidney Cells than in Astrocytes Due to Its More Efficient Involvement in Energy Metabolism

Being among the most metabolically active organs, brain and kidneys critically depend on efficient energy metabolism, which primarily relies on oxidative phosphorylation. Acute pathological conditions associated with a lack of metabolic substrates or their impaired utilization trigger signaling cascades that initiate cell death and lead to poorly reversible organ dysfunction. One of the therapeutic approaches to correct the energy deficit is administration of exogenous metabolites of the tricarboxylic acid cycle, such as succinate. In this study, we investigated the effects of exogenous succinate on astrocytes and renal epithelial cells under normal conditions and in serum deprivation-induced injury. Incubation with succinate increased the viability of both cell types under normal and pathological conditions, but a more pronounced cytoprotective effect was observed in renal cells. In injured renal epithelial cells, succinate increased mitochondrial membrane potential, a critical parameter for the maintenance of mitochondrial function and ATP generation. Comparison of respiration and oxidative phosphorylation parameters in astrocytes and renal epithelial cells in the presence of exogenous succinate revealed that epithelial cells exhibited a significantly higher respiratory control and lower proton leak compared to astrocytes, which correlated with the higher cytoprotective activity of succinate for kidney cells. Therefore, succinate showed a noticeable positive effect in the renal epithelium both under normal conditions and after serum deprivation; however, in astrocytes, its effect was less pronounced. This discrepancy might be related to a more efficient succinate utilization by the mitochondria in renal cells and intrinsic bioenergetic differences between astrocytes and epithelial cells. Despite the clinical use of succinate-containing drugs, the determination of optimal dosages and development of effective therapeutic regimens require further investigation. Our results demonstrate cell type-dependent differences in the efficacy of succinate, suggesting that its therapeutic potential may differ significantly depending on the organ-specific bioenergetic and metabolic properties.