14-3-3ζ constrains insulin secretion in pancreatic β-cells by regulating mitochondrial function

Mugabo, Y.; Zhao, C.; Tan, J. J.; Ghosh, A.; Campbell, S. A.; Fadzeyeva, E.; Pare, F.; Pan, S. S.; Galipeau, M.; Ast, J.; Broichhagen, J.; Hodson, D. J.; Mulvihill, E. E.; Petropoulos, S.; Lim, G. E.

doi:10.1101/2021.10.17.464702

bioRxiv · 10.1101/2021.10.17.464702

14-3-3ζ constrains insulin secretion in pancreatic β-cells by regulating mitochondrial function

Mugabo, Y.·Zhao, C.·Tan, J. J.·Ghosh, A.·Campbell, S. A.·Fadzeyeva, E.·Pare, F.·Pan, S. S.·Galipeau, M.·Ast, J.·Broichhagen, J.·Hodson, D. J.·Mulvihill, E. E.·Petropoulos, S.·Lim, G. E.

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Abstract

While critical for neurotransmitter synthesis in the brain, members of the 14-3-3 protein family are often assumed to have redundant, over-lapping roles due to their high sequence homology and ubiquitous expression. Despite this assumption, various mammalian 14-3-3 isoforms have now been implicated in regulating cellular and organismal metabolism; however, these functions were primarily observed in cell lines or from systemic knockout mouse models. To date, we have begun to define the contributions of 14-3-3{zeta} in adipocytes, but whether 14-3-3{zeta} has additional metabolic roles in other cell types, such as the pancreatic {beta}-cell, is unclear. We previously documented a pro-survival role of 14-3-3{zeta} in MIN6 insulinoma cells, as depletion of 14-3-3{zeta} induced cell death, but paradoxically, whole-body deletion of 14-3-3{zeta} in mice resulted in significantly enlarged {beta}-cell area with no effects on insulin secretion. To better understand the role of 14-3-3{zeta} in {beta}-cells, we generated {beta}-cell-specific 14-3-3{zeta} knockout ({beta}14-3-3{zeta}KO) mice, and while no differences in {beta}-cell mass were observed, {beta}14-3-3{zeta}KO mice displayed potentiated insulin secretion due to enhanced mitochondrial function and ATP synthesis. Deletion of 14-3-3{zeta} led to profound changes to the {beta}-cell transcriptome, where pathways associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute treatment of mouse islets and human islets with pan-14-3-3 inhibitors recapitulated the potentiation in glucose-stimulated insulin secretion (GSIS) and mitochondrial function, suggesting that 14-3-3{zeta} is a critical isoform in {beta}-cells that regulates GSIS. In dysfunctional db/db islets and islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3{zeta}, was inversely associated with insulin secretory capacity, and pan-14-3-3 protein inhibition was capable of enhancing GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3{zeta} and its related isoforms in insulin secretion and mitochondrial function in {beta}-cells. A deeper understanding of how 14-3-3{zeta} influences {beta}-cell function will further advance our knowledge of how insulin secretion from {beta}-cells is regulated.

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Mugabo, Y., Zhao, C., Tan, J. J., Ghosh, A., Campbell, S. A., Fadzeyeva, E., Pare, F., Pan, S. S., Galipeau, M., Ast, J., Broichhagen, J., Hodson, D. J., Mulvihill, E. E., Petropoulos, S., Lim, G. E.. 2021-10-17. 14-3-3ζ constrains insulin secretion in pancreatic β-cells by regulating mitochondrial function. https://doi.org/10.1101/2021.10.17.464702

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