Fig. 9

Ferroptosis as a hyothetical mechanism for the post-COVID-19 trajectory of aging and neurodegeneration. In COVID-19, five shared events can prelude to ferroptosis in post-COVID-19 trajectory. They are 1-Neuroinflammation, 2-Iron dysregulation, 3-Reactive oxygen species (ROS)/antioxidant imbalance, 4- ACE2/Ag II disruption, and 5-Clock gene alteration. 1- The SARS-CoV-2-induced cytokine storm disrupts BBB, which allows pro-inflammatory cytokines to pass to the brain vicinity and activate microglia. Pro-inflammatory ctokines aid the microglia polarization from M2 (anti-inflammatory) to M1 (Pro-inflammatory). 2- IL-6 promotes the production of hepcidin from microglia and astrocytes. Hepcidin degrades FPN1, which traps iron in neurons, microglia, and propably astrocytes. In iron-overloaded microglia, higher LIP causes more microglia polarization and NF-κB helps production of more pro-inflammatory cytokines and activates the iNOS which increases the production of NO. NO passes to neurons and modulates the molecular machinery of iron regulation by upregulating IRP, which causes higher expression of DMT1 and TFR1 and lower expression of ferritin and FPN1. This disruption in iron-related proteins increases the LIP and incites a vicious cycle of iron dysregulation and neuroinflammation. 3- The higher expression of NF-κB decreases the expression of NrF2. The iron overload activates P53. The less NrF2 and more P53 repress the expression of SLC7A11, which decreases the production of GSH. The less NrF2 also can decrease the production of GPX4, compromising the antioxidant system in the face of higher H2O2 and OH^● production caused by NOX and high LIP, respectively. 4- The binding of the spike protein to ACE2 receptors degrades them and Ag II accumulates and binds to ATR1, activating NOX and producing more H2O2. 5- SARS-CoV-2 could induce autophagic degradation/clockophagy of BMAL1 and CLOCK, which is mediated by the cargo receptor SQSTM1/p62. The high LIP, the disruption of ACE2/ATR1, the antioxidant system failure, and BMAL1-CLOCK deficiency all would promote lipid peroxidation and ferroptosis in a progressive manner that would lead to acceleration of aging and neurodegeneration. ROS: reactive oxygen species, ACE2: angiotensin converting enzyme 2 receptors, Ag II: angiotensin II, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, BBB: blood brain barrier, IL-6: interleukin-6, TNF-α: tumor necrosis factor alphs, FPN1: ferroportin, LIP: labile iron pool, NF-κB: nuclear factor-κB, iNOS: inducible nitric oxide synthase, NO: nitric oxide, IRP: iron regulatory protein, IRE: iron responsive element, mRNA: messenger ribonucleic acid, DMT1: divalent metal transporter 1, TFR1: transferrin receptors-1, NrF2: nuclear factor erythroid 2-related factor 2, P53: tumor protein p53, SLC7A11: Solute carrier family 7 member 11, SLC3A2: Solute carrier family 3 member 2, GSH: reduced glutathione, GPX4: glutathione peroxidase 4, H202: hydrogen peroxide, OH^●: hydroxyl radical, PUFA^●: polyunsaturated fatty acid lipid radical, PUFAOOH: lipid hydroperoxide radical, NOX: nicotinamide adenine dinucleotide phosphate oxidase, NADPH: nicotinamide adenine dinucleotide phosphate, ATR1: angiotensin receptor 1, BMAL1: brain and muscle ARNT-like 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1, CLOCK: circadian locomotor output cycles kaput, SQSTM1/p62: sequestosome1