posted on 2021-08-30, 01:16authored byRamkumar 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).