Iron Metabolism and Ferroptosis in Epilepsy

Abstract

Epilepsy is a disease characterized by recurrent, episodic, and transient central nervous system (CNS) dysfunction resulting from an excessive synchronous discharge of brain neurons. It is characterized by diverse etiology, complex pathogenesis, and difficult treatment. In addition, most epileptic patients exhibit social cognitive impairment and psychological impairment. Iron is an essential trace element for human growth and development and is also involved in a variety of redox reactions in organisms. However, abnormal iron metabolism is associated with several neurological disorders, including hemorrhagic post-stroke epilepsy and post-traumatic epilepsy (PTE). Moreover, ferroptosis is also considered a new form of regulation of cell death, which is attributed to severe lipid peroxidation caused by the production of reactive oxygen species (ROS) and iron overload found in various neurological diseases, including epilepsy. Therefore, this review summarizes the study on iron metabolism and ferroptosis in epilepsy, in order to elucidate the correlation between iron and epilepsy. It also provides a novel method for the treatment, prevention, and research of epilepsy, to control epileptic seizures and reduce nerve injury after the epileptic seizure.

Keywords: GPX4; autophagy; cell death; epilepsy; ferroptosis; iron metabolism; post-traumatic epilepsy.

FIGURE 1

Regulatory mechanisms of ferroptosis. Lipid peroxidation leads to ferroptosis. The regulation of lipid peroxidation is related to the following regulation pathways. (1) System Xc^–-CSH-GPX4 pathway, P53-SLC7A11-GPX4 pathway, (2) Akt-Nrf2-GPX4 pathway, GSK3β-NRF2-GPX4 pathway, Se/Zn/Co-GPX4 pathway, (3) Autophagy-dependent ferroptosis: NCOA4-induced ferritinophagy (ferritin is degraded by autophagy), (4) Iron metabolism: p62-Keap1-NRF2-Fe²⁺ regulatory pathway, IREB2-ferritin-Fe²⁺ regulatory pathway. In addition, Fe³⁺ binds to plasma TF to transport iron to all organs, TF delivers iron into cells by binding to TFR1, and Fe³⁺ is released from TF. Fe³⁺ is reduced to Fe²⁺ by STEAP3, (5) FSP1-CoQ10 pathway: the FSP1-CoQ10 pathway directly regulates lipid peroxidation independent of GPX4.

FIGURE 2

Iron ions are involved in the formation of free radicals. ROS originates from Fenton reaction, which is a process of producing OH^– and OH by the reaction of Fe²⁺ and H₂O₂. The Haber–Weiss cycle also shows that Fe³⁺ is reduced to Fe²⁺ through the reaction with O^2–. and Fe²⁺ reacts with H₂O₂ to form OH, OH^–, and Fe³⁺. The electron reaction with O₂ at the mitochondrial electron transport chain produces O^2–. Meanwhile, O^2– can bind hydrogen ions to produce H₂O₂.

FIGURE 3

Glutathione (GSH) and GSSG can be converted to each other in the presence of enzymes. The ratio of GSSG/GSH indicates the degree of oxidative stress in cells. In biological reactions, GSH and GSSG can be converted into each other in the presence of enzymes. GSSG can be converted into GSH using NADPH/H⁺ as a cofactor under the catalysis of GSR, and NADP⁺ can also be converted to NADPH/H⁺. However, under the catalysis of FSP1, NADPH/H⁺ can be converted to NADP⁺, and CoQ10 is converted to CoQ10H₂, which inhibits ferroptosis. GPX4 also converts GSH to GSSG. Moreover, lipid hydroperoxides (R-OOH) are converted to lipid alcohols (R-OH) by GPX4 using reduced GSH.

FIGURE 4

NRF2 regulates the targets related to ferroptosis at the transcriptional level. NRF2 mainly regulates the targets related to ferroptosis at the transcriptional level. These targets regulated by NRF2 can be divided into three broad classes: iron metabolism, intermediate metabolism, and GSH metabolism. However, NRF2 regulates a plethora of target genes involved in iron metabolism [FTH1, FTL, SLC40A1(FPN), HMOX1, ABCB6, FECH, SLC48A1, BLVRA/B, and HO-1], intermediate metabolism [NROB2(SHP), PPARG, AKR1C1-3, G6PD, AKR1B1, ALDH1A1], and GSH metabolism (GPX4, SLC7A11, GCLC/GCLM, GSS, GSTA1, GSTP1, PRDX1/6, and TXNRD1).