{"doi":"10.1101/2021.05.09.443165","title":"iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome","abstract":"Summary Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215904,"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":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":576929,"name":"Kang Jin","orcid":"0000-0001-5638-040X","position":1,"is_corresponding":false},{"id":565074,"name":"Abha Bais","orcid":"0000-0001-5910-1306","position":2,"is_corresponding":false},{"id":733839,"name":"Wenjuan Zhu","orcid":"0000-0003-2724-4825","position":3,"is_corresponding":false},{"id":603533,"name":"Hisato Yagi","orcid":"0000-0003-1460-4043","position":4,"is_corresponding":false},{"id":378614,"name":"Timothy N. Feinstein","orcid":"0000-0002-9801-9708","position":5,"is_corresponding":false},{"id":590689,"name":"Phong K. Nguyen","orcid":null,"position":6,"is_corresponding":false},{"id":811853,"name":"Joseph Criscione","orcid":null,"position":7,"is_corresponding":false},{"id":414132,"name":"Xiaoqin Liu","orcid":"0009-0005-4527-7681","position":8,"is_corresponding":false},{"id":811234,"name":"Gisela Beutner","orcid":"0000-0002-6157-0934","position":9,"is_corresponding":false},{"id":314376,"name":"Kalyani B. Karunakaran","orcid":"0000-0003-1279-7750","position":10,"is_corresponding":false},{"id":791061,"name":"Phillip S. Adams","orcid":"0000-0003-3917-3024","position":11,"is_corresponding":false},{"id":590292,"name":"Catherine K. Kuo","orcid":"0000-0002-8274-418X","position":12,"is_corresponding":false},{"id":394727,"name":"Dennis Kostka","orcid":"0000-0002-1460-5487","position":13,"is_corresponding":false},{"id":12155,"name":"Gloria Pryhuber","orcid":"0000-0002-9185-3994","position":14,"is_corresponding":false},{"id":106180,"name":"Sruti Shiva","orcid":"0000-0003-3535-2113","position":15,"is_corresponding":false},{"id":314378,"name":"Madhavi K. Ganapathiraju","orcid":"0000-0002-3825-0924","position":16,"is_corresponding":false},{"id":54923,"name":"George A. Porter","orcid":"0000-0003-0726-9988","position":17,"is_corresponding":false},{"id":328706,"name":"Jiuann‐Huey Lin","orcid":"0000-0003-3029-6079","position":18,"is_corresponding":false},{"id":71644,"name":"Bruce J. Aronow","orcid":"0000-0001-5109-6514","position":19,"is_corresponding":false},{"id":314377,"name":"Cecilia Lo","orcid":"0000-0003-4314-3434","position":20,"is_corresponding":false},{"id":395386,"name":"Xinxiu Xu","orcid":"0000-0003-3867-5030","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-18T23:53:00.192353Z","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":[]}