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 beta -cells is unexplored. In this study, we identified the role of OGT in mitochondrial function in beta -cells. Constitutive deletion of OGT (beta OGTKO) or inducible ablation in mature beta -cells (i beta OGTKO) causes distinct effects on mitochondrial morphology and function. Islets from beta OGTKO, but not i beta OGTKO, mice display swollen mitochondria, reduced glucose-stimulated oxygen consumption rate, ATP production, and glycolysis. Alleviating endoplasmic reticulum stress by genetic deletion of Chop did not rescue the mitochondrial dysfunction in beta OGTKO mice. We identified altered islet proteome between beta OGTKO and i beta OGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in beta OGTKO islets. Pdx1 overexpression increased insulin content and improved mitochondrial morphology and function in beta OGTKO islets. These data underscore the essential role of OGT in regulating beta -cell mitochondrial morphology and bioenergetics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal beta -cell physiology.

Automated summary

This study identified the role of OGT in regulating beta-cell mitochondrial function, showing that OGT deletion can lead to mitochondrial dysfunction. Furthermore, overexpression of Pdx1 was found to improve mitochondrial function in OGT-deficient cells.