Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

Abstract

<b><i>Background:</i></b> Neurodegenerative diseases are characterized by a gradual decline in motor and/or cognitive function caused by the selective degeneration and loss of neurons in the central nervous system, but their pathological mechanism is still unclear. Previous research has revealed that many forms of cell death, such as apoptosis and necrosis, occur in neurodegenerative diseases. Research in recent years has noticed that there is a new type of cell death in neurodegenerative diseases: ferroptosis. An increasing body of literature provides evidence for an involvement of ferroptosis in neurodegenerative diseases. <b><i>Summary:</i></b> In this article, we review a new form of cell death in neurodegenerative diseases: ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species when glutathione-dependent lipid peroxide repair systems are compromised. Several salient and established features of neurodegenerative diseases (including lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis, which means that ferroptosis may be involved in the progression of neurodegenerative diseases. In addition, as the center of energy metabolism in cells, mitochondria are also closely related to the regulation of iron homeostasis in the nervous system. At the same time, neurodegenerative diseases are often accompanied by degeneration of mitochondrial activity. Mitochondrial damage has been found to be involved in lipid peroxidation and iron dyshomeostasis in neurodegenerative diseases. <b><i>Key Messages:</i></b> Based on the summary of the related mechanisms of ferroptosis, we conclude that mitochondrial damage may affect neurodegenerative diseases by regulating many aspects of ferroptosis, including cell metabolism, iron dyshomeostasis, and lipid peroxidation.

Natural Polysaccharides as Preventive and Therapeutic Horizon for Neurodegenerative Diseases

“…Several salient and established features of neurodegenerative diseases (e.g., lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis [87]. Ferroptosis is defined by Nomenclature Committee on Cell Death as "regulated cell death (RCD) initiated by oxidative perturbations of the intracellular microenvironment that is under constitutive control by Glutathione Peroxidase 4 (GPX4) and can be inhibited by iron chelators and lipophilic antioxidants" [88].…”

Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria

“…All neurodegenerative diseases are characterized by the progressive and irreversible loss of neurons from specific regions of the central and peripheral nervous systems, followed by a decline in neuronal, motor, and/or cognitive functions [ 107 ]. It was shown that cellular death driven by increased levels of iron, ROS, and consequent lipid peroxidation—ferroptosis—is an important contributor to neural cell death in Alzheimer's, Parkinson's, and Huntington's diseases, multiple sclerosis, and acute brain injury caused by cerebral ischemia, haemorrhagic insults, or brain trauma [ 108 – 111 ]. In addition, more recent studies have suggested that mitochondrial damage might be the ultimate step in ferroptosis-related oxidative cell death in neurodegeneration [ 112 ].…”

Mechanisms of Metal-Induced Mitochondrial Dysfunction in Neurological Disorders

“…Although the detailed mechanism by which iron overload promotes ferroptosis has yet to determined, it is reasonable to hypothesize that iron overload may drive the generation of hydroxyl radicals, which further react with liposomes to produce lipid peroxidation products and cause mitochondrial dysfunction, and eventually ferroptosis [ 310 , 311 , 312 ]. Although mitochondria have been shown to be vital regulators of iron homeostasis and ferroptosis in neurodegenerative diseases [ 313 ], more direct evidence targeting iron overload, mitochondrial dysfunction, and ferroptosis is still required. The mitochondria are also the site for the synthesis of iron–sulfur cluster biogenesis (ISCs) and heme prosthetic groups.…”