Ferroptosis as a Novel Therapeutic Target for Friedreich’s Ataxia

Abstract

Friedreich ataxia (FRDA) is a progressive neuro-and cardiodegenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (knockin/knockout) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors ethyl 3-(benzylamino)-4-(cyclohexylamino)benzoate (SRS11-92) and ethyl 3-amino-4-(cyclohexylamino)benzoate, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis [L-buthionine (S,R)-sulfoximine (BSO)], whereas caspase-3 inhibitors failed to show significant biologic activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

“…Along this line, we found a decrease of NRF2 and GPX4, altered expression of genes controlling iron metabolism and increased susceptibility to ferroptosis in brown adipocyte precursors, as well as in mature adipocytes isolated from KIKO mice. These results are in accordance with the findings pointing to oxidative stress, iron overload, and ferroptosis among the main pathogenic factors in FRDA 6,27,[53][54][55] . Interestingly, NRF2, besides being an up-stream modulator of the expression of antioxidant genes and protection against oxidative stress/ferroptosis 56,57 , positively regulates enzymes involved in mitochondrial oxidation of FAs 29 and adipogenesis 58,59 .…”

“…Ferroptosis is a form of ironmediated and lipid-mediated programmed cell death recently implicated in neurodegenerative diseases including FRDA. Notably, increased susceptibility to ferroptosis was found in primary patient-derived fibroblasts and murine fibroblasts from a mouse FRDA model 6 .…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…In FRDA, the expression of the encoded protein frataxin was decreased, leading to obstruction of mitochondrial matrix iron-sulfur cluster biosynthesis, mitochondrial dysfunction, and mitochondrial iron accumulation, and finally result in increased oxidative stress. Studies have found that cells treated with ferric ammonium citrate (FAC) and L-buthionine-sulfoximine (BSO) consistently show reduced GSH-dependent peroxidase activity and increased lipid peroxidation in FRDA disease model (Cotticelli et al, 2019). When comparing the erastin in the induction of ferroptosis in neurons and HT1080 fibrosarcoma cells, it was found that selective protection of neurons by class I histone deacetylase (HDAC) inhibitors and accelerated cancer cell ferroptosis (Zille et al, 2019).…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…Also, it has been demonstrated that ferroptosis is an important cell death pathway for dopaminergic neurons that is regulated by protein kinase C in PD, and that autophagy contributes to ferroptosis by the degradation of ferritin . Ferroptosis has also been considered as a novel therapeutic target for Friedreich's Ataxia, AD, and HD . Since the discovery of the ferroptosis, iron, and ROS have been increasingly acknowledged as crucial initiators and mediators of cell death in a variety of organisms and pathological situations.…”