Integrated immune, apoptotic and mitochondrial gene dysregulation in Long COVID and their association with symptom burden at 10 months post-infection

Long COVID is characterized by persistent symptoms following acute SARS-CoV-2 infection, yet its biological mechanisms remain incompletely understood. Emerging evidence suggests that immune dysregulation, mitochondrial dysfunction, and altered cell survival pathways may contribute to prolonged symptomatology. In this cross-sectional study, peripheral blood mononuclear cells were collected from individuals with Long COVID approximately 10 months post-infection and from recovered individuals without Long COVID symptoms. Symptom burden was assessed using a composite domain-based score. mRNA expression of immune and antiviral genes (IL-6, IL-1β, IL-10, SOCS3, HIF-1α, OAS1, MAVS, IFN-α, IFN-γ), anti-apoptotic markers (MCL1, BCL-2, XIAP, LIVIN), cell cycle kinases (CDK4, CDK6), mitochondrial biogenesis and dynamics markers (NRF1, TFAM, PGC-1α, DRP1, MFN1/2, OPA1), and mitophagy regulators (PARKIN, PINK1) were quantified using quantitative real-time PCR. Data was analyzed by SPSS and GraphPad Prism. Individuals with Long COVID demonstrated significantly higher expressions of IL-6, IL-1β, IL-10, SOCS3, HIF-1α, OAS1, MAVS, NRF1, DRP1, PARKIN, MCL1, and LIVIN compared with recovered controls after using the Benjamini-Hochberg False Discovery Rate (FDR) method. Several transcriptional markers, particularly HIF-1α, IL-1β, IL-10, and NRF1, remained independently associated with symptom burden after adjustment for age and sex. Correlation analysis demonstrated coordinated transcriptional co-expression patterns across immune, antiviral, mitochondrial, and apoptosis-related genes. Long COVID at 10 months post-infection is associated with coordinated transcriptional alterations across multiple biological pathways. The association of these changes with symptom burden suggests a potential link between persistent immunometabolic activation and clinical manifestations. These findings are exploratory and highlight the need for longitudinal and functional studies to further elucidate underlying mechanisms.