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OGT regulates mitochondrial biogenesis and function via diabetes susceptibility gene Pdx1

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posted on 30.08.2021, 01:16 by Ramkumar Mohan, Seokwon Jo, Amber Lockridge, Deborah A. Ferrington, Kevin Murray, Arthur Eschenlauer, Ernesto Bernal-Mizrachi, Yoshio Fujitani, Emilyn U. Alejandro
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. Here, 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 ER 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 over-expression 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.

Funding

This work was supported by the National Institutes of Health (NIH Grant NIDDK R21-DK112144 and R01 DK115720 to EUA, and R01 DK084236 to EBM, and NIH/NEI R01EY028554, R01EY026012 and the Lindsay Family Foundation for DAF).

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