An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia

Abstract

Background: Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Scope of review: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.

Inhibiting Ferroptosis: A Novel Approach for Ulcerative Colitis Therapeutics

“…Frataxin protein, which localizes to mitochondria and is involved in the biosynthesis of iron-sulfur clusters, has recently received the attention of investigators. Decreased frataxin expression can lead to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species, and lipid peroxidation [ 93 ]. These features are also common to ferroptosis.…”

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

“…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.…”

Cerebral Iron Deposition in Neurodegeneration

“…Consequently, Fe-S containing proteins, such as aconitase and respiratory complexes I-III are deficient, resulting in impaired energy metabolism, oxidative damage, and progressive mitochondrial dysfunction. Increasing evidence indicates the presence of ferroptosis markers in FRDA, including increased plasmatic malondialdehyde documenting lipid peroxidation, low levels of glutathione and downregulation of GPX4 implicating lower antioxidant status, upregulation of nuclear receptor coactivator 4 (NCOA4) indicating ferritinophagy, and downregulation of NRF2, which is a natural inhibitor of ferroptosis [262]. Along the same line of thinking, skin fibroblasts from FRDA patients derived from biopsied tissue exhibit higher phototoxicity to UVA radiation caused by an increased mitochondrial labile Fe pool and ROS as compared to healthy controls.…”