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.

Keywords: Friedreich’s Ataxia; ferroptosis; iron; neurodegeneration; oxidative stress.

Figure 1

Iron metabolism and its relationship with ferroptosis. Through the transferrin receptor 1 (TFR1), the iron (Fe³⁺) binds to the transferrin carrier (TF) and is imported into the cell by endocytosis. In the endocytic vesicle, Fe³⁺ is reduced to Fe²⁺ and released in the cytosol, where it is targeted to mitochondria for heme (not shown) and iron–sulfur cluster (ISC) synthesis. The intracellular iron excess is stored in ferritin complexes. The deregulation of red-circled proteins (i.e., TFR1, ferritin and frataxin) can trigger ferroptosis.

Figure 2

Ferroptosis hallmarks in Friedreich’s Ataxia (FA). In FA, the decrease of frataxin expression determines iron accumulation in the mitochondria and impairments in the Fe–S cluster (ISC) biogenesis, leading to a dysfunctional respiratory chain. The Fenton’s reaction-induced increase of ROS determines the lipid peroxidation of membrane polyunsaturated fatty acids (PUFAs). In FA, the cellular antioxidant defense is faulty, and NF-E2 p45-related factor 2 (NRF2) expression and activity are reduced, leading to a decrease of glutathione (GSH) and GPX4, potentially lowering the threshold needed for ferroptosis induction.