COVID-19 Research Perspective Volume 12, Issue 10 pp 8760—8765

Figure 1. Particulate matter air pollution and SARS-CoV-2/COVID-19: A mechanistically linked pathway illuminating a therapeutic opportunity for metformin. Top. Pathological signaling in the lung induced by particulate matter (PM) air pollution partially overlaps with that caused by severe SARS-CoV-2/COVID-19, namely the release of proinflammatory interleukins (e.g., IL-6) from alveolar macrophages via mitochondrial reactive oxygen species (ROS)-driven activation of Ca²⁺ release-activated Ca²⁺ (CRAC) channels, lastly promoting an acceleration of thrombotic events. Patients already experiencing a chronic cytokine response might be at higher risk of COVID-19 lethal complications after SARS-CoV-2 infection. Bottom. Given the linkage between mitochondrial functionality, ion channels, and inflammation in human aging, therapeutic interventions capable of targeting mitochondrial electron transport and prevent mitochondrial ROS/CRAC-mediated IL-6 release (e.g., metformin) might illuminate a preventive/prophylactic mechanism of action to quell the raging of the cytokine and thrombotic-like storms that are the leading causes of COVID-19 morbidity and mortality in older people. In an acute scenario of SARS-CoV-2-driven hyperinflammation, small molecule CRAC channel inhibitors may also be contemplated as a means of treating patients with severe COVID-19 at risk for progressing to typical/atypical ARDS.