Molecular insights into the anti-COVID-19 activity of reduced (quinol) and oxidized (quinone) forms of coenzyme Q10

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, was declared a global pandemic by the World Health Organization in March 2020 and rapidly emerged as a systemic mitochondrial disorder rather than a pure respiratory illness. The disease disrupts mitochondrial bioenergetics, redox balance, and electron transport, with significant impairment of the quinone-quinol pool. Coenzyme Q10 (CoQ10), a central component of the mitochondrial respiratory chain, shuttles electrons between complexes I/II and III through dynamic interconversion between its oxidized quinone (CoQ; QN) and reduced quinol (CoQH 2 ; QL) forms. COVID-19 patients exhibit reduced endogenous CoQ10 levels, defective oxidative phosphorylation, and excessive oxidative stress, linking QN-QL imbalance to inflammation, thrombosis, fatigue, and multi-organ dysfunction. Restoration of mitochondrial redox cycling through CoQ10 supplementation or QN-based bioactive compounds has therefore gained attention as a therapeutic strategy. In this study, we investigated the effects of mitochondrial CoQ10 redox forms on key factors involved in COVID-19 infection using computational analyses and human oral squamous cell carcinoma (HSC3)-based assays. Molecular docking analyses demonstrated that QN binds more strongly than QL to host cell receptors (AR, ACE2, and TMPRSS2), which are key regulators of viral infection. However, cell-based experiments revealed similar effects of both compounds on cell viability, clonogenicity, and the expression of host cell receptors ACE2 and TMPRSS2. Furthermore, similar effects of QN and QL were observed in cells exposed to oxidative, metal, and hypoxic stress. Higher, but not lower, nontoxic concentrations of both compounds led to comparable downregulation of host cell receptors. In contrast, lower doses of QN and QL similarly protected cells against oxidative, metal, and hypoxia stress. These findings suggest that both forms exert similar modulatory effects on host cell receptors and stress-responsive pathways implicated in SARS-CoV-2 pathogenesis, supporting their potential as candidates for further investigation.