Mitochondria and cytokine storm in COVID-19
As mitochondria are shown to be one of the critical components in
eliciting the innate immune response, specifically in response to
viruses, the SARS-CoV-2 mediated immune response could involve
mitochondria. In support of this hypothesis, a master regulator analysis
of combined SARS-CoV-2 specific interactome with MERS and SARS- CoV
transcriptome using the human lung RNA-sequence data set validates the
interaction with ACE-2 and TMPRSS, in addition to certain mitochondrial
proteins (Guzzi, Mercatelli, Ceraolo & Giorgi, 2020). These
mitochondrial proteins are MCL-1, a regulator of apoptosis, as well as
the Complex I subunit NDUFA10 network, which is downregulated (Guzzi,
Mercatelli, Ceraolo & Giorgi, 2020). However, the proposed mechanism is
that the virus strategizes to down-regulate mitochondrial function and
uses host cells for replication. This is not executed by
mitochondrial-dependent elimination, controlling host cell metabolism
and apoptosis. At normal physiological conditions, the MAV protein
present on the mitochondrion’s outer membrane interacts with mitofusin-2
(Mfn2), which is essential for mitochondrial fusion. During viral entry,
mitochondrial associated membranes at the ER tether mitochondria using
Mfn2 and RIG-1. Using other protein recruits, the virus binds to MAVS,
which then induces phosphorylation and nuclear translocation of IRF3,
resulting in the production of cytokines and interferon I/III through
activation of NFKba and IRFs (3/7), respectively (Lin, Heylbroeck, Pitha
& Hiscott, 1998). As in vitro data showed that MAVS is required for the
induction of IFN production by activating NFKb and IRF3, recent evidence
also shows that mice lacking MAVS failed to induce IFN production in
response to viral infection. This suggests the involvement of
mitochondria in the viral-mediated immune response (Sun et al., 2006)
(Figure 3) .
A clue from a previous study carried out in peripheral blood mononuclear
cells (PBMCs) infected with SARS-CoV (Li et al., 2003; Li et al., 2004)
showed that upregulation of genes encoding mtDNA, as well as genes
involved in oxidative stress, heat shock, and transcription, coincides
with cytokine elevation, compared to PBMCs from control samples (Shao et
al., 2006). The mtDNA genes included 16S rRNA (a ribosomal subunit),
NADH dehydrogenase subunit 1 (ND1), and cytochrome c oxidase subunit I
(COX1), whereas the genes involved in oxidative stress are peroxiredoxin
1 (PRDX1) and ferritin heavy polypeptide 1 (FTH1), heat shock response
are DnaJ (Hsp40), homolog subfamily B member 1 (DNAJB1), and cytokine
IL-1B as well (Shao et al., 2006). These SARS-CoV-infected patients are
also shown to have a significantly increased number of mitochondria in
their PBMCs compared to PBMCs from control subjects. This may be one of
the reasons why more mtDNA gene expression is observed. Interestingly,
the electron microscopic structure of PBMCs from SARS-CoV infected
patients showed increased lysosome-like granules, which was not seen in
the control. This could possibly be the activation of mitochondria in
PBMCs, causing an increased immune response and cytokine storm. We
hypothesize that this could be more cell-specific as it depends on
whether the cell is more immunogenic or not. Likewise, a recent study
has shown a similar observation of SARS-CoV-2 infection in PBMCs and
lymphoma along with the cytokine storm, but the involvement of
mitochondria, which is likely, was not investigated in this study (Liu
et al., 2020). This study further showed that cytokines IL-6, IL-10,
IL-2 and IFN-γ are significantly increased in severe COVID-19 cases than
mild cases, displaying that these levels are associated with the disease
severity. Therefore, a possible cytokine storm induced by mitochondria
in COVID-19 could be heterogeneous among the infected population. It
could also be influenced by preexisting metabolic dysfunction, which
further determines the intensity of the cytokine storm and whether it
eliminates the virus or causes multi-organ failure.