The Chemical Biology of Ferroptosis in the Central Nervous System

Abstract

Over the past five decades, thanatology has come to include the study of how individual cells in our bodies die appropriately and inappropriately in response to physiological and pathological stimuli. Morphological and biochemical criteria have been painstakingly established to create clarity around definitions of distinct types of cell death and mechanisms for their activation. Among these, ferroptosis has emerged as a unique, oxidative stress-induced cell death pathway with implications for diseases as diverse as traumatic brain injury, hemorrhagic stroke, Alzheimer's disease, cancer, renal ischemia, and heat stress in plants. In this review, I highlight some of the formative studies that fostered its recognition in the nervous system and describe how chemical biological tools have been essential in defining events necessary for its execution. Finally, I discuss emerging opportunities for antiferroptotic agents as therapeutic agents in neurological diseases.

Excitotoxicity: Still Hammering the Ischemic Brain in 2020

“…Sustained intracellular acidity likely becomes lethal due to myriad disturbances in protein conformation and essential cellular processes (Nedergaard et al, 1991), including energy failure (Swanson et al, 1997). If cellular H + favors release of ferrous iron (Kraig et al, 1987), the Fenton reaction (Jung et al, 2009) may facilitate hydroxy radical formation, lipid peroxidation, and a "ferroptosis" form of regulated cell death (Xie et al, 2016;Ratan, 2020) if necrosis does not supervene. Proton-induced death of cerebellar neurons is accompanied by an increase in [Zn 2+ ] i and reduced by Zn 2+ chelation, raising the possibility that disturbance in Zn 2+ storage or other homeostatic mechanisms may also contribute to H + cytotoxicity (Isaev et al, 2010).…”

Ferroptosis in Neurological Diseases

“…Neurodegenerative diseases include complex and elaborate cell death mechanisms and multiple pathways, which involve excessive accumulation of iron and lipid peroxidation in different brain regions (Guiney et al, 2017). An important feature of nervous system dysfunction is the metabolic and nutritional coupling between glial cells (astroglial cells, oligodendrocytes, and microglia) and neurons, which can lead to neuronal death, especially in ferroptosis (Ratan, 2020). Ferroptosis is dependent on excessive iron accumulation, which is a crucial component of lipid oxidation and is derived from iron metabolism disorder (Cao and Dixon, 2016).…”

“…Human platelet lysates can inhibit ferroptosis and reduce neuronal loss in cellular models of PD and amyotrophic lateral sclerosis (ALS) (Gouel et al, 2017). Third, as another type of inhibitor, Mithramycin, DNA-binding drugs, can reduce c-Myc expression by binding to the Sp1 site in its promoter, thereby playing a role in inhibiting iron death and treating animal models of HD and AD (Sleiman et al, 2011;Ratan, 2020). Fourth, in mouse hippocampal neuron cells, gastrodin inhibits glutamate-induced ferroptosis through the Nrf2/HO-1 signaling pathway (Jiang et al, 2020).…”

“…This exerts further neuroprotective effects and improves acute stroke recovery (Semenza et al, 2000;Bruick, 2003;Siddiq et al, 2005). On the other hand, the possible process of HIF-PHD causing ferroptosis is as follows: when glutathione is depleted, iron released from the disruption of the glutathione-Grx3/Grx4 Fe/S cluster complex could then be taken up into iron chaperones (PCB1) for enzymes such as the HIF PHDs, and then drive the expression of iron-promoting ATF4 gene, thereby causing ferroptosis (Ratan, 2020).…”

Overdosing on iron: Elevated iron and degenerative brain disorders

“…[114][115][116] Because of their unique structure composed of axons and dendrites and consequently high plasma membrane composition, neurons could be particularly sensitive to ferroptosis. 117,118 Ferroptotic death has been detected in a variety of neurodegenerative diseases. 49,118,119 Ferroptosis is often triggered by reduced activity of glutathione peroxidase (GPX4), an enzyme that utilizes glutathione (GSH) as reducing substrate to detoxify highly reactive hydroxyl radical and peroxyl radicals that are produced through the Fenton reaction catalyzed by Fe 2þ .…”