Article révisé par les pairs
Résumé : Ca2+ may trigger apoptosis in beta-cells. Hence, the control of intracellular Ca2+ may represent a potential approach to prevent beta-cell apoptosis in diabetes. Our objective was to investigate the effect and mechanism of action of plasma-membrane Ca2+-ATPase (PMCA) overexpression on Ca2+-regulated apoptosis in clonal beta-cells. Clonal beta-cells (BRIN-BD11) were examined for the effect of PMCA overexpression on cytosolic and mitochondrial Ca2+ concentration [Ca2+] using a combination of aequorins with different Ca2+ affinities, and on the endoplasmic-reticulum (ER) and mitochondrial pathways of apoptosis. beta-cell stimulation generated microdomains of high [Ca2+] in the cytosol and subcellular heterogeneities in [Ca2+] among mitochondria. Overexpression of PMCA decreased [Ca2+] in the cytosol, the ER and the mitochondria. PMCA overexpression activated the IRE1alpha-XBP1s but inhibited the PERK-eiF2alpha-CHOP and the ATF6-BiP pathways of the ER unfolded protein response. Increased Bax/Bcl-2 expression ratio (proapoptotic/antiapoptotic Bcl-2 family members) was observed in PMCA overexpressing beta-cells. This was followed by Bax translocation to the mitochondria with subsequent cytochrome c release, opening of the permeability transition pore, loss of mitochondrial membrane potential and apoptosis. In conclusion, clonal beta-cell stimulation generates microdomains of high [Ca2+] in the cytosol and subcellular heterogeneities in [Ca2+] among mitochondria. PMCA overexpression depletes intracellular [Ca2+] stores and, despite a decrease in mitochondrial [Ca2+], induces apoptosis through the mitochondrial pathway. These data open the way to new strategies to control cellular Ca2+ homeostasis that could decrease beta-cell apoptosis in diabetes.

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