FIGURE 3.

Proposed mechanisms of SARS-CoV-2 mediated increase in mtROS production. When SARS-CoV-2 spike proteins bind to the ACE2 receptor to enter ECs, ADAM17 is thought to be activated and cleave the ACE2 ectodomain, leading to downregulation of ACE2. This leads to an accumulation of Ang II that binds to AT1R, a G-protein-coupled receptor. The binding of Ang II to AT1R activates downstream effectors like c-Src, PKC, and Rac-1, which facilitate assembly and activation of NADPH oxidase. NADPH oxidase produces ${\text{O}}_2^{-}$ that reacts with NO to form ONOO^– and is also converted to H₂O₂ by SOD1. ONOO^– and H₂O₂ both inactivate ETC complexes, which results in increased production of ${\text{O}}_2^{-}$. Mitochondrial SOD2 can then convert ${\text{O}}_2^{-}$ to H₂O₂, which is able to diffuse across membranes. TMPRSS2: transmembrane protease, serine 2; ACE: angiotensin-converting enzyme; ETC: electron transport chain; mtROS: mitochondrial reactive oxygen species; SOD: superoxide dismutase; c-Src: proto-oncogene tyrosine-protein kinase Src; PKC: protein kinase C.