The calcium-iron connection in ferroptosis-mediated neuronal death

Abstract

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.

Keywords: Calcium; Calcium release channels; Ferroptosis; Ferroptosis inhibitors; Iron; Neurodegeneration; Oxidative stress; Reactive oxygen species.