Fixing frataxin: 'ironing out' the metabolic defect in Friedreich's ataxia

Abstract

The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron-sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro- and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies.

Keywords: Friedreich's ataxia; autophagy; cardio- and neurodegeneration; frataxin; mitochondrial iron accumulation; oxidative stress.

Figure 1

Scheme ofcellular iron uptake and utilization. Transferrin-bound iron(III) binds to TfR1 and enters the cell via endocytosis. Acidification of the endosome by a proton pump releases iron from transferrin. Iron(III) is reduced to iron(II) by the ferrireductase, six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3) and then transported through the endosomal membrane by DMT1. Transferrin and TfR1 are recycled back to the cell surface to become available for further iron uptake cycles. Once in the cytosol, iron(II) potentially enters a labile intracellular iron pool (LIP) where it can either (i) be trafficked to the mitochondrion for biosynthesis of essential metabolites; (ii) is potentially chaperoned by PCBPs to cytosolic ferritin for storage; or (iii) exported from the cell via the export pump, Fpn1.

Figure 2

Scheme ofthe ‘kiss and run’ hypothesis of mitochondrial iron uptake from transferrin. This mechanism proposes a route for iron trafficking between the cytosol and the mitochondrion. Iron still bound to transferrin in the endosome is transported by endocytosis to the mitochondrion where it docks by an unknown mechanism and enters the mitochondrion directly. Further studies are required to definitively prove its existence.

Figure 3

Scheme ofthe IRP/IRE mechanism of regulating cellular iron homeostasis. Cellular iron metabolism is regulated by RNA-binding proteins known as IRP1 and 2. The IRPs bind to IREs in the 5′ and 3′ UTRs of mRNAs of molecules responsible for iron homeostasis, for example, TfR1, ferritin, Fpn1, DMT1, etc. The IRE-binding activity of IRP1 and IRP2 are dictated by cellular iron levels by different molecular mechanisms. Under iron-deplete conditions, IRPs bind IREs in the 5′ UTR of ferritin and Fpn1 mRNA suppressing their translation, while IRP binding to the 3′ UTR of TfR1 and DMT1 mRNA stabilize them against degradation. Conversely, under iron-replete conditions, IRP-IRE binding is greatly diminished leading to translation of ferritin and Fpn1 mRNA and the degradation of TfR1.

Figure 4

Scheme offrataxin's effect on cellular redox state. Frataxin-deficient cells exhibit increased sensitivity to oxidative stress. Iron accumulation in the mitochondrion is a potential source of ROS formation in the cell resulting in oxidative stress. This may be due to the proposed role of frataxin in regulating ROS formation by activating cellular antioxidant defences. Nrf2 is down-regulated and Nrf2-regulated antioxidant enzymes from both the glutathione (GSH) and thioredoxin redox systems fail to be activated in frataxin-deficient cells. The combination of increased ROS formation and failure of the cell to neutralize ROS by antioxidant mechanisms may lead to apoptosis and neurodegeneration.

Figure 5

Tissue-specific FRDA pathology.