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Open AccessArticle

Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3

Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada
Faculty Saint-Jean, Department of Medicine, University of Alberta, Edmonton, AB T6C 4G9, Canada
Author to whom correspondence should be addressed.
Cells 2020, 9(1), 168; (registering DOI)
Received: 14 November 2019 / Revised: 3 January 2020 / Accepted: 4 January 2020 / Published: 9 January 2020
(This article belongs to the Collection Functions of Nuclear Receptors)
Nor1, the third member of the Nr4a subfamily of nuclear receptor, is garnering increased interest in view of its role in the regulation of glucose homeostasis. Our previous study highlighted a proapoptotic role of Nor1 in pancreatic beta cells and showed that Nor1 expression was increased in islets isolated from type 2 diabetic individuals, suggesting that Nor1 could mediate the deterioration of islet function in type 2 diabetes. However, the mechanism remains incompletely understood. We herein investigated the subcellular localization of Nor1 in INS832/13 cells and dispersed human beta cells. We also examined the consequences of Nor1 overexpression on mitochondrial function and morphology. Our results show that, surprisingly, Nor1 is mostly cytoplasmic in beta cells and undergoes mitochondrial translocation upon activation by proinflammatory cytokines. Mitochondrial localization of Nor1 reduced glucose oxidation, lowered ATP production rates, and inhibited glucose-stimulated insulin secretion. Western blot and microscopy images revealed that Nor1 could provoke mitochondrial fragmentation via mitophagy. Our study unveils a new mode of action for Nor1, which affects beta-cell viability and function by disrupting mitochondrial networks. View Full-Text
Keywords: diabetes; Nr4a; mitochondria; mitophagy; nuclear receptor; apoptosis; cytokines diabetes; Nr4a; mitochondria; mitophagy; nuclear receptor; apoptosis; cytokines
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Close, A.-F.; Dadheech, N.; Lemieux, H.; Wang, Q.; Buteau, J. Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3. Cells 2020, 9, 168.

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