{"doi":"10.7554/elife.97069","title":"Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren’s disease","abstract":"The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren’s syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca 2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca 2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca 2+ -activated Cl - channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca 2+ . Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca 2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca 2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca 2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca 2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.","journal":"eLife","year":2024,"id":432260,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9465,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":638900,"name":"Larry E. Wagner","orcid":"0000-0002-5631-8697","position":1,"is_corresponding":false},{"id":456812,"name":"Takahiro Takano","orcid":"0000-0002-6235-6673","position":2,"is_corresponding":false},{"id":1237304,"name":"Xiao-Xuan Lin","orcid":null,"position":3,"is_corresponding":false},{"id":415031,"name":"Harini Bagavant","orcid":null,"position":4,"is_corresponding":false},{"id":415032,"name":"Umesh S. Deshmukh","orcid":null,"position":5,"is_corresponding":false},{"id":147718,"name":"David I Yule","orcid":"0000-0002-6743-0668","position":6,"is_corresponding":false},{"id":692223,"name":"Kai‐Ting Huang","orcid":"0000-0003-3138-3406","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:59:35.267142Z","pmid":"39259200","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":[]}