OGT Regulates Mitochondrial Biogenesis and Function via Diabetes Susceptibility Gene Pdx1

O-GlcNAc transferase (OGT), a nutrient sensor sensitive to glucose flux, is highly expressed in the pancreas. However, the role of OGT in the mitochondria of b-cells is unexplored. In this study, we identified the role of OGT in mitochondrial function in b-cells. Constitutive deletion of OGT (bOGTKO) or inducible ablation in mature b-cells (ibOGTKO) causes distinct effects on mitochondrial morphology and function. Islets from bOGTKO, but not ibOGTKO, mice display swollen mito-chondria, reduced glucose-stimulated oxygen con-sumption rate, ATP production, and glycolysis. Alleviating endoplasmic reticulum stress by genetic deletion of Chop did not rescue the mitochondrial dysfunction in bOGTKO mice. We identified altered islet proteome between bOGTKO and ibOGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in bOGTKO islets. Pdx1 overexpression increased insulin content and imp-roved mitochondrial morphology and function in bOGTKO islets. These data underscore the essential role of OGT in regulating b-cell mitochondrial morphology and bioener-getics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal b-cell physiology.