{"doi":"10.1007/s11357-025-01890-5","title":"Germline regulation of the intestinal mitochondrial unfolded protein response","abstract":"Abstract The disposable soma theory posits that there is a trade-off between reproduction and somatic maintenance. In support of this theory, we previously identified that pharmacological inhibition of the germline has widespread protective cell non-autonomous effects on cellular protein homeostasis in the model organism Caenorhabditis elegans . However, the cell non-autonomous effects of the germline on mitochondrial protein homeostasis are not well defined. Here, we use pharmacological or genetic inhibition of the germline to determine its effects on intestinal mitochondrial protein homeostasis as measured by the mitochondrial unfolded protein response (UPR mt ). We find that pharmacological inhibition of germline proliferation by 5-fluoro-2-deoxyuridine (FUdR), a DNA synthesis inhibitor, potently inhibits activation of the intestinal UPR mt as well as reverses lifespan effects induced by mitochondrial dysfunction. We find similar results with the genetic mutant ( glp-1 ), which lacks germline proliferation. To further identify the reproductive processes required to regulate the intestinal UPR mt , we examined the genetic mutant fem-1 , which contains an intact gonad with oocytes but lacks sperm. Like glp-1 mutants, fem-1 mutants do not activate the intestinal UPR mt due to mitochondrial dysfunction caused by loss of OXPHOS subunits. Restoring reproduction in fem-1 mutants by mating them with wild type males is sufficient to reactivate the intestinal UPR mt . Furthermore, loss of the FOXO transcription factor daf-16 is sufficient to reactivate the intestinal UPR mt in fem-1 mutants and partially in glp-1 mutants. These findings suggest that FOXO/ daf-16 acts to limit UPR mt activation in the intestine. These findings also suggest that late-stage reproductive signals that include the maturation of oocytes and fertilization may play a critical role in cell non-autonomous intestinal UPR mt activation.","journal":"GeroScience","year":2025,"id":580408,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1491228,"name":"Nathaniel A. Jordan","orcid":"0009-0004-5441-6164","position":1,"is_corresponding":false},{"id":1491229,"name":"Alan G. Castle","orcid":"0009-0007-7471-1146","position":2,"is_corresponding":false},{"id":229956,"name":"Dipa Bhaumik","orcid":null,"position":3,"is_corresponding":false},{"id":321590,"name":"Julie K. Andersen","orcid":"0000-0003-1324-4875","position":4,"is_corresponding":false},{"id":228996,"name":"Gordon J. Lithgow","orcid":"0000-0002-8953-3043","position":5,"is_corresponding":false},{"id":525743,"name":"Suzanne Angeli","orcid":"0000-0002-6229-9648","position":6,"is_corresponding":false},{"id":565676,"name":"Anna Foulger","orcid":"0000-0003-4135-9741","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T02:58:38.868285Z","pmid":"41204020","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":[]}