COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Abstract

Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

The osteo-metabolic phenotype of COVID-19: an update

“…1 ). These mechanisms include calcium-dependent viral mechanisms of action determining intra and extra-cellular cation dysmetabolism [ 22 – 24 ], tissues calcium deposits detected at autoptic evaluation [ 25 ], acute muscle calcium precipitation [ 26 ], calcium role in coagulation and prothrombotic status [ 27 , 28 ], acute malnutrition during critical illness [ 29 ], high levels of unbound and unsaturated fatty acids in inflammatory responses [ 30 ] and high prevalence of hypovitaminosis D with an impaired compensatory PTH response [ 31 ]. Furthermore, severe hypocalcemia, although not frequently found in COVID-19 [ 3 , 13 ], may compromise outcome per se due to its additional negative cardiovascular and neurological impact [ 3 , 13 ].…”

Pathophysiology of iron and hepcidin metabolism: research perspectives in rheumatolog

“…За последнее время благодаря широкому применению метода иммуноферментного анализа и возможности получения моноклональных антител проведен ряд работ по определению уровня гепсидина при различных болезнях [2,6,15,26]. Так, например, при лимфопролиферативных и инфекционных заболеваниях, в том числе при коронавирусной инфекции (COVID-19), уровень гепсидина значительно превышает нормальные значения, однако наблюдается также и резкое понижение его содержания в сыворотке у ряда больных [29]. Авторы предполагают, что эти изменения связаны с активацией клеток СМФ, поскольку у этих пациентов наблюдалось повышение уровня ферритина сыворотки [29].…”

“…Так, например, при лимфопролиферативных и инфекционных заболеваниях, в том числе при коронавирусной инфекции (COVID-19), уровень гепсидина значительно превышает нормальные значения, однако наблюдается также и резкое понижение его содержания в сыворотке у ряда больных [29]. Авторы предполагают, что эти изменения связаны с активацией клеток СМФ, поскольку у этих пациентов наблюдалось повышение уровня ферритина сыворотки [29]. Эти результаты подтверждают данные о том, что гепсидин не только регулирует метаболизм железа, но и отражает воспалительную активность, а его повышение в сыворотке больных при хроническом воспалении является проявлением острофазового ответа.…”

SARS-CoV-2 infection induces activation of ferroptosis in human placenta

“…Iron overload in cells and tissues coupled with hyperferritinemia has been well documented in patients with severe SARS-CoV-2 infection ( Cavezzi et al, 2020 ; Edeas et al, 2020 ; Fratta Pasini et al, 2021 ; Cavezzi et al, 2022 ), suggesting that the dysregulation of iron metabolism may play an important role in contributing to the pathogenesis of COVID-19. Indeed, while iron constitutes an essential element for all living cells, extra iron can cause overproduction of reactive oxygen species and damage of cellular macromolecules including lipids, nucleic acids, and proteins, thus leading to ferroptosis and multiorgan failure ( Habib et al, 2021 ).…”