{"doi":"10.1101/2020.10.20.347443","title":"Mitohormesis reprograms macrophage metabolism to enforce tolerance","abstract":"Abstract Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, pharmacologically-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria. Abstract Figure","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127535,"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":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":570038,"name":"Kevin M. Tharp","orcid":"0000-0002-3543-3266","position":1,"is_corresponding":false},{"id":576821,"name":"Breanna Ford","orcid":"0000-0001-8277-9406","position":2,"is_corresponding":false},{"id":577826,"name":"Janet M. Winchenster","orcid":null,"position":3,"is_corresponding":false},{"id":576822,"name":"Jerome Wang","orcid":"0000-0003-2767-6177","position":4,"is_corresponding":false},{"id":577827,"name":"Stella Zhu","orcid":null,"position":5,"is_corresponding":false},{"id":577828,"name":"Rida I. Khan","orcid":null,"position":6,"is_corresponding":false},{"id":577829,"name":"Shannon K. Louie","orcid":null,"position":7,"is_corresponding":false},{"id":261600,"name":"Anthony T. Iavarone","orcid":null,"position":8,"is_corresponding":false},{"id":291462,"name":"Johanna ten Hoeve","orcid":"0000-0003-0226-749X","position":9,"is_corresponding":false},{"id":34058,"name":"Daniel K. Nomura","orcid":"0000-0003-1614-8360","position":10,"is_corresponding":false},{"id":576823,"name":"Andreas Stahl","orcid":"0000-0002-9096-3024","position":11,"is_corresponding":false},{"id":572895,"name":"Kaoru Saijo","orcid":"0000-0003-1656-1753","position":12,"is_corresponding":false},{"id":576820,"name":"Greg A. Timblin","orcid":"0000-0001-9351-3646","position":0,"is_corresponding":true}],"reference_count":117,"raw_metadata":null,"created_at":"2026-07-18T23:15:34.966380Z","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":[]}