Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 175, Issue -, Pages 28-41Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.08.231
Keywords
Calcium; Iron; Ferroptosis; Reactive oxygen species; Oxidative stress; Calcium release channels; Neurodegeneration; Ferroptosis inhibitors
Funding
- Agencia Nacional de investigacion y Desarrollo (ANID) [21200346]
- Fondo de Fomento al Desarrollo Cientifico y Tecnologico (FONDEF) [I7I10095, ID20i10234]
- Fondo Nacional De Investigacion Cientifica y Tecnologica (FONDECYT) [1170058]
- Biomedical Neuroscience Institute (BNI) [ICM-09-015-F/ICN_015]
- Bundesministerium fur Bildung und Forschung (BMBF) [180051]
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Iron plays a crucial role in the physiological function of biological systems, particularly in the development of normal cognitive functions in the brain, but its deregulation can lead to neuronal damage and death. Ferroptosis, a newly described iron-dependent cell death pathway, differs morphologically, biochemically, and genetically from other types of cell death. It involves iron-mediated lipid peroxidation, depletion of the endogenous antioxidant glutathione, and altered mitochondrial morphology.
Iron, through its participation in oxidation/reduction processes, is essential for the physiological function of biological systems. In the brain, iron is involved in the development of normal cognitive functions, and its lack during development causes irreversible cognitive damage. Yet, deregulation of iron homeostasis provokes neuronal damage and death. Ferroptosis, a newly described iron-dependent cell death pathway, differs at the morphological, biochemical, and genetic levels from other cell death types. Ferroptosis is characterized by iron-mediated lipid peroxidation, depletion of the endogenous antioxidant glutathione and altered mitochondrial morphology. Although iron promotes the emergence of Ca2+ signals via activation of redox-sensitive Ca2+ channels, the role of Ca2+ signaling in ferroptosis has not been established. The early dysregulation of the cellular redox state observed in ferroptosis is likely to disturb Ca2+ homeostasis and signaling, facilitating ferroptotic neuronal death. This review presents an overview of the role of iron and ferroptosis in neuronal function, emphasizing the possible involvement of Ca2+ signaling in these processes. We propose, accordingly, that the iron-ferroptosis-Ca2+ association orchestrates the progression of cognitive dysfunctions and memory loss that occurs in neurodegenerative diseases. Therefore, to prevent iron dyshomeostasis and ferroptosis, we suggest the use of drugs that target the abnormal Ca2+ signaling caused by excessive iron levels as therapy for neurological disorders.
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