{"doi":"10.1101/2022.04.14.487897","title":"p66Shc is an apoptotic rheostat whose targeted ROS inhibition improves MI outcomes","abstract":"SUMMARY p66Shc is an oxidoreductase that responds to cell stress by translocating to mitochondria, where p66Shc produces pro-apoptotic reactive oxygen species (ROS). This study identifies ROS-active p66Shc as a monomer that produces superoxide anion independent of metal ions, inhibits cytochrome c peroxidase, and is regulated by environmental condition-induced structural changes. p66Shc anti-apoptotic functions, including: cytochrome c reduction, increased electron transport chain activity, and caspase cascade inhibition were also discovered. This study also demonstrates that p66Shc is a stress-dependent rheostat of apoptosis, regulated by p66Shc-mortalin complexes. These complexes decrease pro-apoptotic ROS production, without blocking p66Shc-mediated cytochrome c reduction. However, stress disrupts p66Shc-mortalin interactions, promoting apoptosis. Tipping p66Shc’s apoptotic balance toward anti-apoptotic functions by genetic knockdown or p66Shc-selective ROS inhibition decreased pro-apoptotic effects and improved outcomes in zebrafish myocardial infarction models, representing a potential new myocardial infarction treatment with promising results.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298622,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"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":987637,"name":"Jennifer M. Johnson","orcid":"0000-0001-5855-7352","position":1,"is_corresponding":false},{"id":987990,"name":"Hannah Schmitz","orcid":null,"position":2,"is_corresponding":false},{"id":321524,"name":"Satoshi Matsuzaki","orcid":"0009-0009-1846-3429","position":3,"is_corresponding":false},{"id":687000,"name":"Virginie Sjoelund","orcid":"0000-0002-7929-5950","position":4,"is_corresponding":false},{"id":244704,"name":"Stephanie D. Byrum","orcid":"0000-0002-1783-3610","position":5,"is_corresponding":false},{"id":321527,"name":"Kenneth M. Humphries","orcid":"0000-0002-6167-3175","position":6,"is_corresponding":false},{"id":442224,"name":"J. Kimble Frazer","orcid":"0000-0003-2936-2817","position":7,"is_corresponding":false},{"id":399433,"name":"Borries Demeler","orcid":"0000-0002-2414-9518","position":8,"is_corresponding":false},{"id":955770,"name":"Doris M. Benbrook","orcid":"0000-0001-7606-8245","position":9,"is_corresponding":false},{"id":987991,"name":"Ryan M. Tierney","orcid":null,"position":10,"is_corresponding":false},{"id":987992,"name":"Kelli D. Duggan","orcid":null,"position":11,"is_corresponding":false},{"id":987638,"name":"Franklin A. Hays","orcid":"0000-0002-2191-558X","position":12,"is_corresponding":false},{"id":987636,"name":"Landon Haslem","orcid":"0000-0003-3359-9147","position":0,"is_corresponding":true}],"reference_count":153,"raw_metadata":null,"created_at":"2026-07-19T00:31:36.269611Z","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":[]}