Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic β-cells. Senescence and activation of a senescence-associated secretory phenotype (SASP) in β-cells may contribute to T1D pathogenesis; however, the mechanisms responsible for this phenotype are not well understood. We hypothesized that loss of endoplasmic reticulum (ER) Ca2+ induces mitochondrial dysfunction and drives the development of β-cell senescence during T1D. To test this hypothesis, we generated sarco/ER Ca2+-ATPase 2 (SERCA2) haploinsufficient mice on the NOD background (NOD-S2+/-). NOD-S2+/- mice displayed accelerated T1D onset compared to NOD-WT mice (14 wks vs 18 wks; p≤ 0.0001 female and 21 wks vs 24.5 wks male; p<0.05). As expected, basal ER Ca2+ levels were reduced in NOD-S2+/- islets, but basal mitochondrial Ca2+ levels were elevated compared to NOD-WT islets. Basal cytoplasmic Ca2+ levels remained unchanged. Single cell RNA sequencing showed an increase in immune cell markers in the NOD-S2+/- islets at 6 wks of age, with signatures of ER stress and mitochondrial dysfunction at both 6 and 10 wks of age. Islets from prediabetic female NOD-S2+/- mice showed decreased glucose-stimulated O2 consumption, reduced ATP production, and decreased mitochondrial membrane potential. Additionally, protein expression of ATP synthase and Complex III was decreased in female NOD-S2+/- islets, but mitochondrial content was unchanged. There was an increased expression of multiple markers of senescence and SASP in NOD-S2+/- islets between 6 and 12 wks of age compared to NOD-WT islets. Lastly, in vivo allosteric activation of SERCA decreased insulitis and delayed diabetes onset in WT NOD mice. Our results show that SERCA2 deficiency leads to mitochondrial dysfunction, β-cell senescence, and accelerated T1D development. In future studies, we will test whether senolytic agents can delay diabetes onset and rescue mitochondrial health in models of T1D and SERCA2 deficiency.
S. A. Weaver: Employee; Eli Lilly and Company. R. N. Bone: None. D. J. Acri: None. J. Kim: None. T. Kono: None. R. Dahl: None. D. L. Eizirik: None. F. Syed: None. C. Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc.
National Institute of Diabetes and Digestive and Kidney Diseases (F31DK134168, R01DK093954, R01DK127308, R01DK127236, UC4DK104166, U01DK127786); U.S. Department of Veterans Affairs (I01BX001733, 2I01BX001733-05); JDRF (3-PDF-2017-385-A-N, 3-IND-2022-1235-I-X); National Center for Advancing Translational Sciences (UL1TR002529)