Fig. 3: Schematic illustration of redox imbalance in the endothelial cell upon infection with SARS-CoV-2.

A The redox imbalance in the endothelial cell occurs through AngII/AT1R/Nox axis pathway. TMPRSS2 cleaves and activates the SARS-CoV-2 spike protein (S) for membrane fusion. SARS-CoV-2 interacts with the ACE2 receptor and is taken up by the cell through endocytosis. The interaction of viral glycoproteins with ACE2 receptor leads to downregulated expression of ACE2, thereby increasing the level of angiotensin II (Ang II). The reduced ACE2 activity may facilitate Ang II binding to the type 1 angiotensin receptor (AT1R). SARS-CoV-2 causes activation of NADPH oxidase, which results in the production of reactive oxygen species (ROS). The ROS generated from the NADPH oxidase are engaged in processes that cause damage to the electron transport chain (ETC) leading to DNA damage in mitochondria as well as in the nucleus. The ROS injury to mitochondrial DNA (mtDNA) may cause mitochondrial dysfunction by impairing ETC complex formation. The mtROS also promote the activation of the different redox signaling pathways and induce the production of various inflammatory cytokines. B Apoptosis induction by the SARS-CoV-2 infection through both the extrinsic and the extrinsic pathways. SARS-CoV-2 may cause apoptosis by the extrinsic route, which involves the cleavage of Bid to tBid (truncated Bid) by activated caspase-8. This cleavage activates mitochondrial outer membrane permeabilization (MOMP) effector proteins BAX and BAK. The MOMP permits executioner caspases to enhance apoptosis. It also triggers the release of mitochondrial cytochrome C, which in turn triggers activation of caspase-9 and leads to apoptosis. (Figure prepared with Biorender).