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.
Highlights
Friedreich’s ataxia (FRDA) is an inherited autosomal recessive neurodegenerative disorder caused by the expansion of a GAA triplet-repeat sequence within the first intron of FXN gene, leading to a decrease of frataxin (FXN) [1], a mitochondrial protein involved in the synthesis of iron-sulphur clusters (Fe-S), which are essential for the activity of mitochondrial respiratory chain complexes I, II, and III, Krebs cycle enzyme aconitase and other mitochondrial enzymes [2]
FRDA is characterized by altered lipid metabolism that leads to accumulation of intracellular lipids in the form of lipid droplets (LDs)
We have highlighted that many of the typical markers of ferroptosis are found in FRDA
Summary
FRDA is an inherited autosomal recessive neurodegenerative disorder caused by the expansion of a GAA triplet-repeat sequence within the first intron of FXN gene, leading to a decrease of frataxin (FXN) [1], a mitochondrial protein involved in the synthesis of iron-sulphur clusters (Fe-S), which are essential for the activity of mitochondrial respiratory chain complexes I, II, and III, Krebs cycle enzyme aconitase and other mitochondrial enzymes [2]. Mitochondrial energy imbalance, accumulation of mitochondrial iron, uncontrolled production of reactive oxygen species (ROS) and increased lipid peroxidation have been implicated in the pathogenesis of the disorder [5]. Such events resemble to those occurring in a new type of cell death firstly described in 2012 by Dixon et al that is, ferroptosis [6]. Even though the accumulation of mitochondrial iron, the increase of oxidative stress and lipid peroxidation found in several cell types with FXN deficiency (e.g., neurons from mouse models and fibroblasts from FRDA patients) [9,10,11,12] are basically the distinctive hallmarks of ferroptosis, a possible link between FRDA and ferroptosis is emerging only recently. We highlight the hallmarks of ferroptosis in FRDA and how improving the knowledge of this iron-dependent cell death could be useful to understand the molecular mechanisms of FRDA and envisage novel therapeutic approaches
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