Host mitochondrial apoptotic signatures in children with chronic conditions reveal viral modulation of MCL-1 in severe SARS-CoV-2 infection

BACKGROUND: Although pediatric SARS-CoV-2 infection is usually mild; children with chronic conditions are at increased risk of severe disease. Myeloid Cell Leukemia-1 (MCL-1), a key regulator of mitochondrial apoptosis, is expressed as one anti-apoptotic isoform (MCL-1 L) and two pro-apoptotic isoforms (MCL-1 S and MCL-1ES), but their regulation in pediatric viral infections remains unclear. METHODS AND RESULTS: 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 S and MCL-1ES showed good-to-excellent accuracy for predicting mild and moderate disease. CONCLUSIONS: 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.