Non-enzymatic RNA Glycation Links Metabolic Stress to Ribotoxic Stress Response and β-Cell Dysfunction

While methylgloxal, a reactive glycolytic byproduct, was shown to modify and regulate proteins and DNA function in diabetes, whether and how metabolic stress directly impacts RNA has remained unclear. Here, we identify RNA, especially mRNA, as a dynamic target of MGO regulated by DJ-1 and the glyoxalase system. mRNA glycation impairs translation and activates both the integrated stress response (ISR) and ribotoxic stress response (RSR).

In particular, mRNA MGO-glycation-dependent activation of the RSR directly impairs pancreatic β-cell function and insulin secretion, which is mitigated by the antihyperglycemic drug metformin. Together, these findings establish mRNA as a metabolic stress sensor and identify RNA glycation as a mechanistic link between glycolytic imbalance, translational stress, and β-cell dysfunction.