{"doi":"10.1101/2022.01.20.477147","title":"SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level","abstract":"Abstract Cardiac manifestations are commonly observed in COVID-19 patients and prominently contributed to overall mortality. Human myocardium could be infected by SARS-CoV-2, and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are susceptible to SARS-CoV-2 infection. However, molecular mechanisms of SARS-CoV-2 gene-induced injury and dysfunction of human CMs remain elusive. Here, we find overexpression of three SARS-CoV-2 coding genes, Nsp6, Nsp8 and M, could globally compromise transcriptome of hPSC-CMs. Integrated transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with hPSC-CMs of Nsp6, Nsp8 or M overexpression identified concordantly activated genes enriched into apoptosis and immune/inflammation responses, whereas reduced genes related to heart contraction and functions. Further, Nsp6, Nsp8 or M overexpression induce prominent apoptosis and electrical dysfunctions of hPSC-CMs. Global interactome analysis find Nsp6, Nsp8 and M all interact with ATPase subunits, leading to significantly reduced cellular ATP level of hPSC-CMs. Finally, we find two FDA-approved drugs, ivermectin and meclizine, could enhance the ATP level, and ameliorate cell death and dysfunctions of hPSC-CMs overexpressing Nsp6, Nsp8 or M. Overall, we uncover the global detrimental impacts of SARS-CoV-2 genes Nsp6, Nsp8 and M on the whole transcriptome and interactome of hPSC-CMs, define the crucial role of ATP level reduced by SARS-CoV-2 genes in CM death and functional abnormalities, and explore the potentially pharmaceutical approaches to ameliorate SARS-CoV-2 genes-induced CM injury and abnormalities.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":305629,"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":0.9573,"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":999475,"name":"Yucheng Zhang","orcid":"0009-0000-9901-6376","position":1,"is_corresponding":false},{"id":737598,"name":"Shiyong Wu","orcid":"0000-0002-4104-4160","position":2,"is_corresponding":false},{"id":999476,"name":"Lei Han","orcid":"0000-0002-0707-5027","position":3,"is_corresponding":false},{"id":999477,"name":"Chéng Wáng","orcid":"0000-0002-0178-8317","position":4,"is_corresponding":false},{"id":300844,"name":"Sheng Liu","orcid":"0000-0002-6409-9519","position":5,"is_corresponding":false},{"id":435370,"name":"Edward Simpson","orcid":"0000-0001-9015-9864","position":6,"is_corresponding":false},{"id":404142,"name":"Ying Liu","orcid":"0000-0002-6540-0473","position":7,"is_corresponding":false},{"id":999478,"name":"Yue Wang","orcid":"0000-0002-4181-9018","position":8,"is_corresponding":false},{"id":458336,"name":"Weinian Shou","orcid":"0000-0001-5538-9605","position":9,"is_corresponding":false},{"id":999479,"name":"Yunlong Liu","orcid":"0000-0002-2214-9637","position":10,"is_corresponding":false},{"id":448584,"name":"Michael Rubart‐von der Lohe","orcid":null,"position":11,"is_corresponding":false},{"id":300846,"name":"Jun Wan","orcid":"0000-0001-9286-6562","position":12,"is_corresponding":false},{"id":999480,"name":"Lei Yang","orcid":"0000-0002-3494-8161","position":13,"is_corresponding":false},{"id":303050,"name":"Juli Liu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:32:41.290883Z","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":[]}