Mitochondria and iron dysregulation in COVID-19
Mitochondria are the hub for iron metabolism, and since iron is
associated with various physiological and pathological roles, it is not
surprising that iron dysregulation is observed in patients with
SARS-CoV-2 infection (Huang et al., 2020; Mehta et al., 2020; Phua et
al., 2020). As iron is an essential element in cells, its role in oxygen
transfer, electron transfer or accepting, and signaling are necessary
for normal physiological functions. Most iron is normally stored in the
form of ferritin in the Ferric state (Fe3+). Iron is required for
optimal mitochondrial function, which primarily utilizes the iron stored
in ferritin and involved in Fe-S cluster biosynthesis for heme synthesis
(Levi & Rovida, 2009). Many of the mitochondrial enzymes involved in
metabolism and oxidative phosphorylation contain an Fe-S cluster, which
helps in facilitating oxidation-reduction reactions (Levi & Rovida,
2009; Rouault, 2016).
Hyperferritinimea is a condition reported in COVID-19 patients where
there is an excess presence of iron beyond the average level in the
blood (Huang et al., 2020; Mehta et al., 2020; Phua et al., 2020). A
large number of studies conducted during the early stages of the
COVID-19 pandemic clearly show the association between blood ferritin
levels and the severity of the disease pathology. Patients who tested
positive for SARS-CoV-2 had higher levels of ferritin compared to those
who had tested negative. Specifically, severe cases of COVID-19 had 1.5
to 5.3 times mores ferritin in the blood compared to mild cases
(Gomez-Pastora et al., 2020). On the other hand, it’s been reported that
COVID-19 non-survivors showed 3-4 times more serum ferritin levels
compared to survivors (Gomez-Pastora et al., 2020). Interestingly, there
was a strong correlation between ferritin and cytokine levels (ex.,
IL-6) with disease severity (Gomez-Pastora et al., 2020; Zhou et al.,
2020). Such correlation explains a possible feedback mechanism where
inflammation-induced cytokines increase the secretion of ferritin,
majorly through iron overloaded cells (ex., macrophages)(Ganz, 2012).
But the functional consequences of elevated ferritin are not clear. As
expected, ferritin levels went down in patients who recovered from
COVID-19, showing that ferritin could be a potential biomarker in
tracing the severity of the inflammatory reaction, including in COVID-19
patients. Hyperferritinimea is also reported in other viral diseases
such as Dengue (van de Weg et al., 2014). It is not clear whether the
high ferritin is a defense mechanism or if it is destructive. However,
it is wise to speculate that it could be defensive at acute or low
levels of elevation but become dangerous when it is secreted in excess.
Although the consequences of increased ferritin in serum on
mitochondrial function are unclear, the overall iron dysregulation
increased serum levels is expected to reduce mitochondrial Fe levels.
This could reduce mitochondrial respiration overall and upregulate
anaerobic respiration, resulting in glycolysis mediated lactic acid
accumulation, which is consistent with the upregulation of Lactate
dehydrogenase in COVID-19 cases (Henry et al., 2020). Therefore,
iron-dependent dysregulation of mitochondria could have serious
consequences that may potentiate COVID-19 pathologies if left untreated.