{"doi":"10.1101/2022.05.30.493783","title":"Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity","abstract":"SUMMARY Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of mtDNA detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability leads to Z-form mtDNA accumulation. Z-DNA Binding Protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Increased mitochondrial Z-DNA, ZBP1 expression, and IFN-I responses are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":296783,"datarank":0.9141938811800827,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.4725280343051166,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.4725280343051166,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":18,"citers_with_citation_signal":17,"citers_with_endowment":17,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":813430,"name":"Jordyn J. VanPortfliet","orcid":"0000-0002-2210-4914","position":1,"is_corresponding":false},{"id":984080,"name":"Yifan Chen","orcid":"0000-0003-2080-843X","position":2,"is_corresponding":false},{"id":571386,"name":"Joshua D. Bryant","orcid":"0000-0001-6668-1409","position":3,"is_corresponding":false},{"id":984081,"name":"Ying Li","orcid":"0000-0002-6775-5649","position":4,"is_corresponding":false},{"id":984814,"name":"Danielle Fails","orcid":null,"position":5,"is_corresponding":false},{"id":571198,"name":"Sylvia Torres-Odio","orcid":"0000-0002-0008-0798","position":6,"is_corresponding":false},{"id":229284,"name":"Katherine B. Ragan","orcid":null,"position":7,"is_corresponding":false},{"id":829649,"name":"Jingti Deng","orcid":null,"position":8,"is_corresponding":false},{"id":984082,"name":"A Mohan","orcid":"0000-0002-9695-2852","position":9,"is_corresponding":false},{"id":285502,"name":"Bing Wang","orcid":"0000-0003-0431-8449","position":10,"is_corresponding":false},{"id":984815,"name":"Olivia N. Brahms","orcid":null,"position":11,"is_corresponding":false},{"id":984816,"name":"Shawn D. Yates","orcid":null,"position":12,"is_corresponding":false},{"id":984817,"name":"Michael Spencer","orcid":null,"position":13,"is_corresponding":false},{"id":571387,"name":"Carl Tong","orcid":"0000-0003-2479-2498","position":14,"is_corresponding":false},{"id":13279,"name":"Marcus Bosenberg","orcid":"0000-0003-0166-1612","position":15,"is_corresponding":false},{"id":571388,"name":"Laura Ciaccia West","orcid":"0000-0002-8303-3582","position":16,"is_corresponding":false},{"id":483253,"name":"Gerald S. Shadel","orcid":"0000-0003-2899-8717","position":17,"is_corresponding":false},{"id":586828,"name":"Timothy E. Shutt","orcid":"0000-0001-5299-2943","position":18,"is_corresponding":false},{"id":225736,"name":"Jason W. Upton","orcid":"0000-0002-4218-4026","position":19,"is_corresponding":false},{"id":264702,"name":"Pingwei Li","orcid":"0000-0002-1815-3107","position":20,"is_corresponding":false},{"id":571201,"name":"A. Phillip West","orcid":"0000-0003-2884-6895","position":21,"is_corresponding":false},{"id":571199,"name":"Yuanjiu Lei","orcid":"0000-0002-7486-4261","position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:21.257700Z","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":[]}