Iron homeostasis imbalance and ferroptosis in brain diseases

Abstract

Brain iron homeostasis is maintained through the normal function of blood-brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients' outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron-dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

Keywords: ferroptosis; iron chelators; iron homeostasis; neurodegenerative diseases; stroke.

FIGURE 1

Metabolic processes of iron transport by transcellular pathway (endocytosis), lipid peroxidation related to the occurrence of ferroptosis, and the body's representative antioxidant system. The Fenton reaction stimulated by liable iron induces lipid peroxidation, while intracellular GSH is insufficient to resist it due to the rapid rise of liable iron so ferroptosis occurs due to the rupture of the unstable membrane. Tf, transferrin; TfR, transferrin receptor; DMT1, divalent metal transporter 1; FPN, ferroportin; Cp, ceruloplasmin; Hp, hephaestin; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, oxidized glutathione; GPX4, glutathione peroxidase 4.

FIGURE 2

Timeline of microglia and iron after hemorrhage stroke (A) and ischemic stroke (B). These timelines are based on the data from the male rat model of AIS and HS., , , Iron deposition in hemorrhage stroke is more rapid than in ischemic stroke due to the release of iron by the dissolution of mass red blood cells. The microglia numbers decrease (the red cycle) in the peri‐hematoma area shortly after HS, which might ascribe to necroptosis, and apoptosis caused by iron release from the hematoma, and significantly increase and peak at days 3−7. In contrast, microglia numbers in the core infarct area reach the peak during days 7−14 after IS and return to normal after day 28. Therefore, the reaction speed and proliferation ability of microglia cells were stronger in hemorrhage stroke, leading to an earlier peaking time of microglia proliferation as well as the earlier switch of the microglial phenotype (M1–M2).

FIGURE 3

The three phases of lipid peroxidation. (i) Initiation is the process that generates radical compounds (PLOOH/PLOO•) from nonradical molecules (PL‐PUFA). (ii) Propagation, starting from lipid peroxides (PLOOH), is a peroxidative chain reaction giving rise to new radicals while the number of radicals remains constant. (iii) Termination is the process in which the peroxidative chain is broken by donating electrons to radical compounds so that transferring the active product (radical compounds) to a stable one (PL‐OH). It should be noted that the iron‐involved Fenton reaction, which participates in the process of initiation and propagation, is a free electron provider. PUFA, polyunsaturated fatty; ACSL4, acyl‐CoA synthetase long‐chain family member 4; PUFA‐CoA, coenzyme A‐activated polyunsaturated fatty acid; LPCAT3, lysophosphatidylcholine acyltransferase 3; PL‐PUFA/PL/PL'H, phospholipids containing polyunsaturated fatty acids; LOX, lipoxygenase; PLOO•, phospholipid peroxy radical; PLOOH, phospholipid hydroperoxide; PLO•, the phospholipid alkoxyl radical; GSH, glutathione; GSSG, oxidized glutathione; Fer‐1, ferrostatin‐1; PL‐OH, phospholipid hydroxides.

FIGURE 4

A generalization of the pathogenesis of brain iron accumulation in ischemic stroke, hemorrhagic stroke, Alzheimer's disease, and Parkinson's disease. Stroke greatly increases the import of brain iron, resulting in iron accumulation. In contrast, the progression of neurodegeneration and iron accumulation are mutually reinforcing. Mass labile iron, as a central link in stroke and neurodegenerative diseases, involves in the Fenton reaction and triggers the imbalance between the oxidation reaction and the antioxidant system in the neurological system, which leads to ferroptosis and then poor outcomes for patients. Tf, transferrin; TfR, transferrin receptor; NTBI, nontransferrin‐bound iron; Fpn, ferroportin; Cp, ceruloplasmin; FtMt, mitochondrial ferritin; MHC‐I, major histocompatibility complex class I; APP, amyloid precursor protein; ARF6, ADP ribosylation factor 6; p‐tau, phosphorylated tau; BBB, the blood–brain barrier; AQP4, aquaporin‐4. Note: "+ in the red cycle” means to promote.