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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2608-2625 |
| Number of pages | 18 |
| Journal | Diabetes |
| Volume | 70 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2021 |
Bibliographical note
Funding Information:The authors thank Dr. David Bernlohr (University of Minnesota) for discussion; Minnesota Supercomputing Institute for an Updraft Grant, which supported the analysis of the proteomics data; Drs. Leann Higgins and Todd Markowski at the University of Minnesota Proteomic Core and Gail Celio from the University Imaging Center; and Brian Akhaphong and Alicia Wong (University of Minnesota) for technical support.
Funding Information:
Acknowledgments. The authors thank Dr. David Bernlohr (University of Minnesota) for discussion; Minnesota Supercomputing Institute for an Updraft Grant, which supported the analysis of the proteomics data; Drs. Leann Higgins and Todd Markowski at the University of Minnesota Proteomic Core and Gail Celio from the University Imaging Center; and Brian Akhaphong and Alicia Wong (University of Minnesota) for technical support. Funding. This work was supported by the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases grants R21DK112144 and R01 DK115720 to E.U.A., grant R01 DK084236 to E.B.-M., and National Institutes of Health/National Eye Institute grants R01EY028554 and R01EY026012 and the Lindsay Family Foundation to D.A.F.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. R.M. and E.U.A. designed experiments, analyzed data, interpreted the data, and wrote and edited the final manuscript. R.M., S.J., A.L., K.M., and A.E. generated and analyzed data and edited the final manuscript. D.A.F. and Y.F. provided resources and edited the final manuscript. E.B.-M. provided resources and contributed to the discussion. E.U.A. conceived the study, designed experiments, interpreted the data, wrote and edited the manuscript, and acquired funding. E.U.A. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. This study was presented at the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 22–26 June 2018.
Publisher Copyright:
© 2021 by the American Diabetes Association.
