Objectives: Metabolic substrate deficiency is a key factor in many pathologies, with organ vulnerability depending on specialized metabolic profiles. In this study, we aimed to investigate the impact of deprivation stress on mitochondria and cell functions in different cell types and to assess the potential of fumarate, a tricarboxylic acid (TCA) cycle intermediate, to modulate these stress responses. Methods: We assessed the effects of fumarate on cell proliferation and mitochondrial membrane potential under both normal conditions and serum deprivation in vitro in astrocytes, renal epithelial cells, and hepatic stellate cells. Subsequently, we performed bioinformatic analysis of transcriptomic data for brain, kidney, and liver tissues subjected to ischemia to reveal specific patterns of alterations in energy metabolism. Results: Analysis of mitochondria-associated gene expression revealed striking organ-specific differences in transcriptional responses to ischemia, with a significant decrease in expression of genes related to the TCA cycle and electron transport chain in the kidneys and liver, in contrast to the brain. In an in vitro serum deprivation model, fumarate preserved mitochondrial potential in a cell type-specific manner, with optimal concentrations of 12.5 mM for astrocytes (p < 0.05), and 25 mM for renal (p < 0.01) or hepatic cells (p < 0.01). Under normal conditions, fumarate increased mitochondrial potential in astrocytes (p < 0.0001), with weak or no effect on renal and hepatic cells. Estimation of cell number indicates the effects of fumarate on the proliferation of kidney (p < 0.05) and liver (p < 0.0001) cells in normal conditions and cell death after serum deprivation. Conclusion: Bioinformatic analysis demonstrates that ischemic stress induces fundamentally different transcriptional programs in the brain, kidney, and liver, particularly affecting genes involved in mitochondrial bioenergetics. Complementing these findings, our in vitro data identify fumarate as a metabolically active but organ-dependent candidate for tissue protective strategies in substrate deprivation pathologies, like ischemia.
Buyan et al. (Thu,) studied this question.