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Myeloid Cell Leukemia-1 (MCL-1), a key regulator of mitochondrial apoptosis, is expressed as one anti-apoptotic isoform (MCL-1\u00a0L) and two pro-apoptotic isoforms (MCL-1\u00a0S and MCL-1ES), but their regulation in pediatric viral infections remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We assessed MCL-1 isoform expression by RT-qPCR and circulating protein levels by ELISA in 324 unvaccinated children (179 SARS-CoV-2-positive and 145 SARS-CoV-2-negative), most with chronic conditions. Statistical analyses included parametric and non-parametric tests, correlation analysis, ROC curves, and multinomial logistic regression. All MCL-1 isoforms were upregulated in respiratory viral infections compared with healthy controls. In contrast, SARS-CoV-2 infection showed attenuated MCL-1 transcript induction, suggesting impaired mitochondrial apoptotic signaling, whereas non-SARS-CoV-2 viruses and coinfections induced robust upregulation. Among SARS-CoV-2-positive patients, MCL-1ES predominated, with increased expression in 95% of subgroups and higher levels in boys, adolescents, and coinfected participants. Chronic conditions, particularly cancer, were major drivers of MCL-1 dysregulation. MCL-1\u00a0S and MCL-1ES showed good-to-excellent accuracy for predicting mild and moderate disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The proposed MCL-1 isoform ratio including MCL-1ES, strongly predicted disease progression, conferring a 6.5- to 7.6-fold increased risk of critical illness, whereas absence of chronic conditions reduced this risk by 94.8%. In addition to chronic medical conditions, this study identified dysregulated MCL-1 isoform balance as a potential determinant of adverse pediatric SARS-CoV-2 outcomes, and supports mitochondrial apoptosis modulation as a host pathway exploited by SARS-CoV-2 and potentially by other viruses with similar immune evasion strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-026-11885-w","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T08:17:28Z","timestamp":1778314648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Host mitochondrial apoptotic signatures in children with chronic conditions reveal viral modulation of MCL-1 in severe SARS-CoV-2 infection"],"prefix":"10.1007","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6659-2043","authenticated-orcid":false,"given":"Emilly Henrique","family":"dos Santos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2543-2796","authenticated-orcid":false,"given":"Gabriel Acca","family":"Barreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2985-8085","authenticated-orcid":false,"given":"Mariana Okay","family":"Saippa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6034-920X","authenticated-orcid":false,"given":"Lucas Augusto Moys\u00e9s","family":"Franco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3577-1801","authenticated-orcid":false,"given":"Mussya Cisotto","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1520-4650","authenticated-orcid":false,"given":"Kelly Aparecida","family":"Kanunfre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8844-8245","authenticated-orcid":false,"given":"Maria Fernanda Badue","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0940-7793","authenticated-orcid":false,"given":"Heloisa Helena Sousa","family":"Marques","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9316-7288","authenticated-orcid":false,"given":"Thelma Suely","family":"Okay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"11885_CR1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1515\/bmc-2016-0015","volume":"7","author":"J Hatok","year":"2016","unstructured":"Hatok J, Racay P (2016) Bcl-2 family proteins: master regulators of cell survival. 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Informed consent and age-appropriate assent were obtained. Procedures followed the Declaration of Helsinki (October 2024 version). In the present study, participants were enrolled by pediatric infectious disease specialists MFBD and HHSM after obtaining written informed consent from parents and informed assent from school-age children and adolescents at the Emergency Departament, and a second time 6\u20138 days after the first evaluation.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Understanding why some children, particularly those with chronic medical conditions, are more likely to develop severe or critical COVID-19 remains a major gap in pediatric knowledge. This study provides the first comprehensive evaluation of MCL-1 isoform dynamics in a large cohort of unvaccinated pediatric patients with respiratory infections, revealing how SARS-CoV-2 uniquely disrupts mitochondrial apoptosis pathways. By demonstrating that specific MCL-1 isoforms and their ratio correlate strongly with disease severity and risk of clinical deterioration, this study uncovers mechanistic insights into how SARS-CoV-2 subverts mitochondrial checkpoints to evade host immunity. Importantly, these findings offer promising biomarkers that may help clinicians stratify risk early, anticipate severe progression, and tailor monitoring and treatment strategies for children, especially those with complex chronic conditions who are more vulnerable to adverse outcomes.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Importance of the Study"}}],"article-number":"731"}}