Mitochondria and inflammatory response in COVID-19
Identifying the critical players of sepsis and inflammatory response resulting from SARS-CoV-2 infection is essential to developing better diagnostic and therapeutic strategies as well. It is known that during sepsis, the infected bacteria release their DNA, which, along with the other proteins, are recognized as pathogen-associated molecular patterns (PAMPs), which stimulate the inflammatory response in the host cells. In this process, released DNA binds to the toll-like receptor 9 (TLR) and the formyl peptides bind to the formyl peptide receptor-1 (FPR1) on the surface of host cells. This further releases cytokines through activation of p38 MAP kinase (MAPK) and attracts neutrophils while establishing immune response activation (Dorward, Lucas, Chapman, Haslett, Dhaliwal & Rossi, 2015). On the other hand, a similar pattern is also observed with no infection, but any trauma or damage to the system by external stimuli could result in the release of molecules called damage-associated molecular patterns (DAMPs), which could initiate an inflammatory response similar to PAMPs. A breakthrough study by Zhang group found that mitochondria are evolutionarily conserved bacteria, sharing a similar structural motif with prokaryotes. They could release their DNA (mtDNA) and peptides (formyl peptides), which are recognized as DAMPS similar to PAMPs, suggesting that bacteria and mitochondria use a similar tactic while eliciting an immune response. Some of the DAMPs released by the mitochondria are mtDNA, TFAM, formyl peptides and ROS (Goulopoulou, Matsumoto, Bomfim & Webb, 2012; Wenceslau, McCarthy, Goulopoulou, Szasz, NeSmith & Webb, 2013; Wenceslau, McCarthy, Szasz, Goulopoulou & Webb, 2015; Zhang et al., 2010). Specifically, formyl peptides are present only in bacteria and mitochondria in nature, suggesting that the injury response caused by DAMPs is analogous to sepsis caused by bacterial infection. Furthermore, these groups showed that intravenous injection of mitochondrial DAMPs caused severe systemic inflammation, including severe lung injury (Zhang et al., 2010), which is most commonly observed in COVID-19 (Chen et al., 2020; Li, Huang, Wang, Ingbar & Wang, 2020; Zhang, Wang, Huang & Wang, 2020). Also, the ATP required for immune cells comes from mitochondria, whereas calcium buffering and ROS are critical components regulated by mitochondria for antigen-presenting, processing and activation of signaling pathways containing inflammatory proteins (Carr et al., 2010; Le et al., 2012). Specifically, in T cells, the deficiency of mitochondrial transcription factor TFAM causes energy deficiency, resulting in T cell metabolic failure. This induces the circulation of cytokines, thereby establishing chronic inflammation and senescence phenotype (Desdin-Mico et al., 2020). Additionally, autophagy, which is a mechanism in which viruses and their proteins are eliminated by being presented to lysosomes is impaired during mitochondrial dysfunction in SARS-CoV/CoV-2, resulting in decreased autophagy in T cells, thereby establishing the infection (Baixauli et al., 2015). This is in agreement with the observation of life-threatening casualties in COVID-19 subjects with metabolic compromised preexisting conditions such as cancer (Liang et al., 2020; Robilotti et al., 2020), heart diseases (Bohm, Frey, Giannitsis, Sliwa & Zeiher, 2020; Guo et al., 2020; Montone, Iannaccone, Meucci, Gurgoglione & Niccoli, 2020), diabetes (Zhu et al., 2020a), aging (Palaiodimos et al., 2020), obesity (Anderson et al., 2020; Klang, Kassim, Soffer, Freeman, Levin & Reich, 2020; Lighter et al., 2020; Palaiodimos et al., 2020) and COPD (Lippi & Henry, 2020), all which are reported in the SARS-CoV-2 infection.