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.