The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models

Abstract

Friedreich's ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from Saccharomyces cerevisiae; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.

Keywords: Friedreich’s ataxia; animal models; frataxin; iron; iron chelators; lipid deregulation; oxidative stress.

FIGURE 1

Frataxin deficiency leads to a series of alterations in the activity and/or expression of different iron-related proteins. Among the most relevant changes observed in humans and FRDA models, there is an increase in the activity of the iron regulatory proteins IRP1 and IRP2, upregulation of TFR1 (transferrin receptor 1) and the mitochondrial iron importer MFRN2 (mitoferrin-2), and downregulation of the iron exporter FPN (ferroportin) and iron storage proteins FRTs (ferritins, light and heavy chains). TF, transferrin; DMT1, divalent metal transporter 1.

FIGURE 2

In Friedreich ataxia patients, deposits of iron in NS have not been clearly reported and it remains a controversial topic, while some evidences point to a relocation of iron from neurons to glial cells. So far there are some hypotheses that explain the possible mechanisms of iron toxicity that lead to cellular dysfunction. The ROS-dependent hypothesis proposes the iron-mediated catalysis of ROS by Fenton reaction. Besides the impairment in ISC synthesis due to frataxin deficiency, the radical species can in turn damage the ISC of proteins generating new free iron that will participate in the Fenton reaction. Contributing to this cycle is the observation that the Nrf2 signaling is defective in some cells and models of the disease. Another recent hypothesis, independent of ROS production, was explored in Drosophila and mouse models. It suggests that the cellular dysfunction can be due to the activation of the PDK1/Mef2 (3-phosphoinositide dependent protein kinase-1/myocyte enhancer factor-2) pathway by means of an increase in sphingolipids synthesis. Both hypothesis as well as the relevance of ROS in the pathology of FRDA have partial support, since the evidence pointing to them vary depending on the study.