Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection

Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2–induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial–immune remodeling in SARS-CoV-2–infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15–MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial–immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection.