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OGT Regulates Mitochondrial Biogenesis and Function via Diabetes Susceptibility Gene Pdx1.
- Source :
-
Diabetes [Diabetes] 2021 Nov; Vol. 70 (11), pp. 2608-2625. Date of Electronic Publication: 2021 Aug 30. - Publication Year :
- 2021
-
Abstract
- 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 β-cells is unexplored. In this study, we identified the role of OGT in mitochondrial function in β-cells. Constitutive deletion of OGT (βOGTKO) or inducible ablation in mature β-cells (iβOGTKO) causes distinct effects on mitochondrial morphology and function. Islets from βOGTKO, but not iβOGTKO, 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 βOGTKO mice. We identified altered islet proteome between βOGTKO and iβOGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in βOGTKO islets. Pdx1 overexpression increased insulin content and improved mitochondrial morphology and function in βOGTKO islets. These data underscore the essential role of OGT in regulating β-cell mitochondrial morphology and bioenergetics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal β-cell physiology.<br /> (© 2021 by the American Diabetes Association.)
- Subjects :
- Animals
Electron Transport
Electron Transport Chain Complex Proteins genetics
Electron Transport Chain Complex Proteins metabolism
Genetic Predisposition to Disease
Glucose Tolerance Test
Homeodomain Proteins genetics
Insulin Secretion
Mice
Mice, Knockout
N-Acetylglucosaminyltransferases genetics
Proteomics
Trans-Activators genetics
Diabetes Mellitus, Type 2 genetics
Homeodomain Proteins metabolism
Mitochondria metabolism
N-Acetylglucosaminyltransferases metabolism
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 70
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 34462257
- Full Text :
- https://doi.org/10.2337/db21-0468