Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

Abstract

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

“…However, unlike the expected activation of the NRF2-mediated antioxidant defense, the NRF2 signaling pathway is defective in FRDA patients and in preclinical models of FXN deficiency ( Paupe et al, 2009 ; Shan et al, 2013 ; La Rosa et al, 2020a , b ), thus further exacerbating the susceptibility to oxidative stress and its induced defects in the disease ( Abeti et al, 2018 ; La Rosa et al, 2020c , d ).…”

“…Oxidative stress is a common condition in many neurodegenerative disorders ( Barnham et al, 2004 ), and in FRDA, in particular, it represents one of the most peculiar, although not completely understood, aspects of the pathology ( Lupoli et al, 2018 ). The GAA repeat-mediated FXN depletion leads to mitochondrial iron accumulation in the disease, causing reactive oxygen species (ROS) generation and lipid peroxidation ( La Rosa et al, 2020c ; Turchi et al, 2020a ). As NRF2 regulates many genes directly involved in counteracting oxidative stress and NRF2 signaling axis is defective in FRDA ( Paupe et al, 2009 ; Cuadrado et al, 2019 ; Petrillo et al, 2019 ), the evaluation of NRF2 expression in this family can help to open a window on new protective factors potentially buffering the FRDA symptomatology.…”

Interchangeable utilization of metals: New perspectives on the impacts of metal ions employed in ancient and extant biomolecules

“…In inherited blood disorders, such as -thalassemia and sickle cell disease, mutations in hemoglobin subunit beta prohibit accommodation of iron causing iron overload (249). Mutation in the FXN gene that encoding frataxin, the protein involved in Fe-S clusters assembly (250), cause Friedreich's ataxia (spinocerebellar degeneration) that is also associated with iron overload (251). Another autosomal recessive disease, the Wilson disease (also known as hepatolenticular degeneration), affects primarily the liver and basal ganglia of the brain, and is caused by mutations in the ATP7B gene and generation of defective copper transport protein leading to copper build up (252,253).…”

Mitochondrial iron and calcium homeostasis in Friedreich ataxia

“…For instance, neurodegeneration in frataxin‐deficient flies and mice has been linked to the activation of the Pdk1/Mef2 pathway, which could be triggered by an increased synthesis of sphingolipids caused by iron overload 54,55 . It has also been proposed that frataxin depletion would lower the threshold of susceptibility to ferroptosis induction 56 . Ferroptosis is a form of regulated cell death, which is triggered by the accumulation of lipid peroxidation products in membranes that cause membrane integrity loss.…”