Ferroptosis and central nervous system demyelinating diseases

Abstract

Ferroptosis is a newly discovered programmed cell death caused by intracellular iron excess and glutathione (GSH) system imbalance, resulting in fatal lipid peroxidation. It is different from necrosis, apoptosis, autophagy, and other forms of cell death. Accumulating evidences suggest that brain iron overload is involved in the pathogenesis of demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS), neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM). The study of ferroptosis may provide a new understanding of demyelinating diseases and provide a novel therapeutic target for clinical treatment. Herein, we reviewed recent discoveries on mechanisms of ferroptosis, the effects of metabolic pathways on ferroptosis, and its involvement in CNS demyelinating diseases.

Cognitive Impairment in Multiple Sclerosis

“…Ferroptosis, also an important mediator of the programmed cell death pathway, has been recently linked to MS and cognitive loss [169,293,294]. Ferroptosis results in intracellular iron accumulation and loss of glutathione homeostasis [295].…”

“…Autophagy pathways are also critical for impacting neurodegeneration and usually involve the blockade of mTOR activity for neuroprotective pathways [17,22,44,70,100,105,169,[242][243][244]259,293]. The induction of autophagy, which may require an mTOR blockade, can protect neuronal and non-neuronal cells [10,24,73,89,106,172,224,442].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…Additional programmed cell death pathways, such as ferroptosis and pyroptosis, also can be important during metabolic disorders. Ferroptosis involves iron storage pathways that block glutathione homeostasis [8,232,233,249,[400][401][402]. The loss of oxidative defenses that require glutathione during ferroptosis leads to memory loss [8,122,232], neuronal and glial cell dysfunction [59,172,400], cardiac impairment [2,403], osteoarthritis [233], and disorders in the tissue of the breast [169].…”

“…Ferroptosis involves iron storage pathways that block glutathione homeostasis [8,232,233,249,[400][401][402]. The loss of oxidative defenses that require glutathione during ferroptosis leads to memory loss [8,122,232], neuronal and glial cell dysfunction [59,172,400], cardiac impairment [2,403], osteoarthritis [233], and disorders in the tissue of the breast [169]. Pyroptosis, which can work in conjunction with necroptosis and apoptosis [41, 59,269,304,404,405], leads to inflammatory cell activation, inflammasome generation, and caspase 4, caspase 5, and caspase 1 activation [8,221,311,404,[406][407][408][409].…”