Dysfunction of SERCA pumps as novel mechanism of methylglyoxal cytotoxicity

Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1

“…To date, multifaceted actions of MGO have been demonstrated in inducing stress responses and contributing to cell death [ [9] , [10] , [11] ]. These include modification of proteins by non-enzymatic glycation and oxidation reactions [ 10 ], irreversible effects on protein misfolding [ 12 ], induction of autophagy flux [ 13 ], activation of matrix metalloproteinases [ 14 ] and dysfunction of SERCA pump [ 15 ]. In our previous study, we found that MGO can induce retinal pigment epithelial ARPE-19 cell death through a reactive oxygen species (ROS)-dependent manner, involving mitochondrial membrane potential (MMP) loss and intracellular calcium increases [ 16 ].…”

Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca2+ release from the ER

“…We also found that the Ca 2+ concentration in the ER was decreased after glucose stimulation by overexpression of UCP2 in INS1 cells. Because methylglyoxal has been shown to impair the activity of SERCA, a calcium pump in the ER, without any changes of protein levels of SERCA ( Zizkova et al., 2018 ), increased methylglyoxal in βUCP2Tg islets might decrease ER Ca 2+ uptake through SERCA. In MIN6 mouse β-cell lines, Ca 2+ uptake through SERCA after high glucose stimulation was inhibited by oligomycin, an inhibitor of ATP synthase ( Moore et al., 2011 ), thus the reduction in ATP production in βUCP2Tg islets might affect SERCA activity.…”