AGE-RAGE/NF-κB/SIRT3 signaling cascade is implicated in mitochondrial dysfunction in diabetic gastroparesis

Abstract Diabetic gastroparesis is a severe complication of diabetes mellitus, yet its underlying molecular mechanisms remain poorly understood. This study investigated how advanced glycation end products (AGEs) trigger mitochondrial dysfunction through NF-κB activation and SIRT3 suppression in diabetic gastroparesis. We analyzed clinical samples from diabetic gastroparesis patients and healthy controls. Primary gastric smooth muscle cells were treated with AGEs to examine cellular responses. The pathogenic role of NF-κB activation and SIRT3 suppression was investigated using pharmacological inhibition and genetic manipulation. A streptozotocin (STZ)-induced diabetic mouse model was used to validate therapeutic approaches targeting AGE-RAGE interaction and mitochondrial function. Clinical samples from diabetic gastroparesis patients showed elevated AGEs levels, activated NF-κB signaling, suppressed SIRT3 expression, and mitochondrial structural abnormalities. In vitro studies revealed that AGEs induced NF-κB activation and SIRT3 suppression, leading to mitochondrial dysfunction and impaired smooth muscle cell contractility. While NF-κB inhibition prevented AGE-induced dysfunction, SIRT3 overexpression protected mitochondrial function despite persistent NF-κB activation. Direct mitochondrial functional restoration also prevented AGE-induced contractile dysfunction. In the diabetic mouse model, both AGE-RAGE blockade and mitochondrial protection improved gastroparesis symptoms. Our findings suggest a potential pathogenic signaling axis whereby AGE-RAGE activation may contribute to NF-κB-mediated SIRT3 suppression, which is associated with mitochondrial dysfunction in the context of diabetic gastroparesis. These observations raise the possibility that targeting AGE-RAGE signaling or supporting mitochondrial function may represent candidate therapeutic strategies for this condition.