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.