Differential effects of diphenyl diselenide (PhSe)2 on mitochondria-related pathways depending on the cellular energy status in Bovine Vascular Endothelial Cells

Cellular energy metabolism varies depending on tissue and cell type, as well as the availability of energy substrates and energy demands. We recently investigated the variations in cellular metabolism and antioxidant responses in primary bovine vascular endothelial cells (BAECs) under different energetic substrate conditions in vitro, specifically glucose or galactose. In this context, pharmacological agents may affect cells differently depending on their energy metabolism status. In this study, we aimed to characterize the effects of diphenyl diselenide ((PhSe)2), a redox-active molecule known for its prominent cardiovascular effects, on redox-bioenergetic cellular pathways under glycolytic or oxidative conditions in BAECs. Under glucose conditions, (PhSe)2 positively impacted mitochondrial oxidative capacity, as assessed by respirometry, and was associated with changes in mitochondrial cellular dynamics. However, these changes were not observed in cells cultured with galactose. Although (PhSe)2 induced the nuclear translocation of the redox sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) in both glucose and galactose media, Nrf2 remained in the nuclei of cells cultured in galactose for a longer duration. Additionally, activation of another redox sensitive transcription factor, forkhead O3 (FOXO3a) was only detected in galactose media. Notably, (PhSe)2 induced the expression of genes controlling mitochondrial antioxidant capacity and glutathione synthesis and recycling in glucose media, whereas its effects in galactose media were primarily focused on glutathione homeostasis. In conclusion, our findings underscore the critical influence of cellular metabolic status on the antioxidant capacity of redox-active molecules such as (PhSe)2.