The role of oxidative ER stress in the dysregulation of ER calcium homeostasis and β-cell failure under type 2 diabetes metabolic conditions
Final Report Abstract
Our modern lifestyle, characterized by high-calorie diets and insufficient physical activity, has led to a global rise in obesity. Consequently, the prevalence of diseases such as type 2 diabetes mellitus (T2DM) has increased significantly. Whereas T2DM previously affected primarily adults, there is now a growing incidence among children and adolescents. This trend creates substantial challenges for healthcare systems while also imposing a significant burden on families affected by the disease. A central risk factor for the development of T2DM is obesity, which is associated with elevated concentrations of saturated fatty acids in the blood—most notably palmitic acid (PA). Chronic exposure to high levels of PA can damage and finally destroy the insulin-producing beta cells of the pancreas, a process known as lipotoxicity. A key mechanism underlying this process is the increased formation of reactive oxygen species (ROS), particularly hydrogen peroxide (H2O2). These ROS are generated during the catabolism of PA in peroxisomes and mitochondria, as well as in the endoplasmic reticulum (ER) during protein folding. Our experimental data demonstrate that PA significantly elevates H2O2 concentrations within the ER, thereby substantially contributing to the induction of ER stress and beta cell death. A critical observation is that PA induced H2O2 inhibits the activity of the sarco/endoplasmic reticulum Calcium-ATPase (SERCA), an enzyme responsible for transporting calcium ions into the ER. As a consequence of SERCA inhibition, calcium levels within the ER levels drop severely, while abnormal accumulation of calcium within the mitochondria occurs. Calcium depletion in the ER impairs the function of numerous protein-folding chaperones and leads to the accumulation of misfolded proteins, further exacerbating ER stress. Conversely, mitochondrial calcium overload disrupts mitochondrial function and promotes beta cell death. The enzyme ERO-1α (endoplasmic reticulum oxidoreductin 1α), which plays a crucial role in protein folding, has been identified as an important source of H2O2 production in the ER. Upon exposure to PA, ERO-1α is markedly upregulated, resulting in increased H2O2 generation. This disrupts the redox balance within the ER and amplifies ER stress, suggesting that oxidative stress and ER stress are not merely parallel phenomena but are closely interconnected and mutually reinforcing. This hypothesis is supported by our findings that enhancing antioxidative defense status, such as expression of the H2O2-eliminating enzyme glutathione peroxidase 8 in the ER or specific genetic deletion of ERO-1α, significantly attenuates the deleterious effects of PA. Both measures reduced H2O2 levels in the ER, stabilized calcium homeostasis, and preserved insulin production in the presence of PA. Thus, H₂O₂ plays a key role in the dysregulation of calcium homeostasis and associated ER stress, which ultimately leads to beta cell dysfunction and destruction. Targeted reduction of H2O2 levels, either by enhancing the antioxidant capacity of the ER or by specifically inhibiting ERO-1α, may therefore represent a promising strategy to protect beta cells from PA-mediated damage.
Publications
-
Differential effects of saturated and unsaturated free fatty acids on ferroptosis in rat β-cells. The Journal of Nutritional Biochemistry, 106, 109013.
Krümmel, Bastian; von Hanstein, Anna-Sophie; Plötz, Thomas; Lenzen, Sigurd & Mehmeti, Ilir
-
Luminal H2O2 promotes ER Ca 2+ dysregulation and toxicity of palmitate in insulin‐secreting INS‐1E cells. The FASEB Journal, 37(1).
Sharifi, Sarah; Böger, Maren; Lortz, Stephan & Mehmeti, Ilir
-
Oxidative ER stess in beta cells: the role of ERO-1α in palmitate- mediated toxicity. 58th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia, 65(S1), 1-469.
Sharifi S. & Mehmeti I.
-
The role of luminal H2O2 in ER Ca2+ dysregulation and toxicity of palmitate in insulin-secreting INS-1E cells. 58th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia, 65(S1), 1-469.
Mehmeti I., Sharifi S., Böger M. & Lortz S.
-
Die Bedeutung von ER-Oxidoreduktin-1α für die Palmitinsäure-vermittelte Dysregulation der Ca2+-Homöostase in pankreatischen Betazellen. Diabetologie und Stoffwechsel, 18(S 01), S20-S20.
Sharifi, Sarah & Mehmeti, Ilir
-
Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of β-cells by upregulating ERO-1α expression. Redox Biology, 73, 103170.
Sharifi, Sarah; Yamamoto, Tomoko; Zeug, Andre; Elsner, Matthias; Avezov, Edward & Mehmeti, Ilir
