{"doi":"10.1101/2021.10.17.464702","title":"14-3-3ζ constrains insulin secretion by regulating mitochondrial function in pancreatic β-cells","abstract":"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 14-3-3ζ in adipocytes, but whether 14-3-3ζ has additional metabolic roles in other cell types, such as the pancreatic β-cell, is unclear. We previously documented a pro-survival role of 14-3-3ζ in MIN6 insulinoma cells, as depletion of 14-3-3ζ induced cell death, but paradoxically, whole-body deletion of 14-3-3ζ in mice resulted in significantly enlarged β-cell area with no effects on insulin secretion. To better understand the role of 14-3-3ζ in β-cells, we generated β-cell-specific 14-3-3ζ knockout (β14-3-3ζKO) mice, and while no differences in β-cell mass were observed, β14-3-3ζKO mice displayed potentiated insulin secretion due to enhanced mitochondrial function and ATP synthesis. Deletion of 14-3-3ζ led to profound changes to the β-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 14-3-3ζ is a critical isoform in β-cells that regulates GSIS. In dysfunctional db/db islets and islets from type 2 diabetic donors, expression of Ywhaz / YWHAZ , the gene encoding 14-3-3ζ, 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 14-3-3ζ and its related isoforms in insulin secretion and mitochondrial function in β-cells. A deeper understanding of how 14-3-3ζ influences β-cell function will further advance our knowledge of how insulin secretion from β-cells is regulated.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221833,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":41897,"name":"C Zhao","orcid":"0000-0001-5825-2401","position":1,"is_corresponding":false},{"id":823006,"name":"JJ Tan","orcid":null,"position":2,"is_corresponding":false},{"id":823007,"name":"A Ghosh","orcid":null,"position":3,"is_corresponding":false},{"id":823008,"name":"SA Campbell","orcid":null,"position":4,"is_corresponding":false},{"id":823009,"name":"E Fadzeyeva","orcid":null,"position":5,"is_corresponding":false},{"id":823010,"name":"F Paré","orcid":null,"position":6,"is_corresponding":false},{"id":823011,"name":"SS Pan","orcid":null,"position":7,"is_corresponding":false},{"id":823012,"name":"M Galipeau","orcid":null,"position":8,"is_corresponding":false},{"id":823013,"name":"J Ast","orcid":null,"position":9,"is_corresponding":false},{"id":823014,"name":"J Broichhagen","orcid":null,"position":10,"is_corresponding":false},{"id":823015,"name":"DJ Hodson","orcid":null,"position":11,"is_corresponding":false},{"id":823016,"name":"EE Mulvihill","orcid":null,"position":12,"is_corresponding":false},{"id":823017,"name":"S Petropoulos","orcid":null,"position":13,"is_corresponding":false},{"id":823018,"name":"GE Lim","orcid":null,"position":14,"is_corresponding":false},{"id":823005,"name":"Y Mugabo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-18T23:53:59.302331Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}