Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation

Abstract

Various human disorders are associated with misdistribution of iron within or across cells. Friedreich ataxia (FRDA), a deficiency in the mitochondrial ironchaperone frataxin, results in defective use of iron and its misdistribution between mitochondria and cytosol. We assessed the possibility of functionally correcting the cellular properties affected by frataxin deficiency with a siderophore capable of relocating iron and facilitating its metabolic use. Adding the chelator deferiprone at clinical concentrations to inducibly frataxin-deficient HEK-293 cells resulted in chelation of mitochondrial labile iron involved in oxidative stress and in reactivation of iron-depleted aconitase. These led to (1) restoration of impaired mitochondrial membrane and redox potentials, (2) increased adenosine triphosphate production and oxygen consumption, and (3) attenuation of mitochondrial DNA damage and reversal of hypersensitivity to staurosporine-induced apoptosis. Permeant chelators of higher affinity than deferiprone were not as efficient in restoring affected functions. Thus, although iron chelation might protect cells from iron toxicity, rendering the chelated iron bioavailable might underlie the capacity of deferiprone to restore cell functions affected by frataxin deficiency, as also observed in FRDA patients. The siderophore-like properties of deferiprone provide a rational basis for treating diseases of iron misdistribution, such as FRDA, anemia of chronic disease, and X-linked sideroblastic anemia with ataxia. IntroductionHumoral factors or mutations of genes that affect iron metabolism often result in pathologic changes linked to systemic or cellular misdistribution of iron. In anemia of chronic disease (ACD), 1 plasma iron deficiency results from retention of iron in the reticuloendothelial system because of hepcidin-mediated inhibition of iron export into plasma. 2 Defective delivery and distribution of iron resulting from deficiency in the iron-chaperone protein frataxin are also considered to be key causative factors in Friedreich ataxia (FRDA). 3,4 The disease is expressed in individuals carrying a GAA repeat expansion in the first intron of frataxin that reduces frataxin levels, leading to reduced iron-sulfur cluster (ISC)-protein (ISP) synthesis and a combined deficiency in aconitase and respiratory chain (complex I-III) activity. This leads to a concomitant deficiency in cell respiratory functions 5 that is further exacerbated by mitochondrial iron accumulation and ensuing oxidative damage. 6,7 FRDA is a neurodegenerative disorder that is often accompanied by hypertrophic cardiomyopathy and increased predisposition for diabetes mellitus. 8 The precise role of iron in FRDA pathophysiology has hitherto remained controversial. 9 Support for its direct involvement in the disease is based on histopathologic examination of human specimens and magnetic resonance imaging of patients. 10 Similar conclusions were drawn from biochemical studies with frataxin-deficient yeast and animal cell models. 11 The contending ...

Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia

“…Deferiprone and deferasirox both access labile cardiac iron, and both appear to be superior to deferoxamine in this regard. 33 One possibility for the ejection fraction improvement seen with deferiprone may be that it prevents iron-related mitochondrial damage, 34 which could result in earlier restoration of mitochondrial function and ATP production, which are required for normal myocyte contraction. This accords with clinical experience that an improvement in ejection fraction may precede changes in T2*, with the former reflecting acute relief of toxicity and the latter measuring storage iron.…”

Continued improvement in myocardial T2* over two years of deferasirox therapy in -thalassemia major patients with cardiac iron overload

“…16 Maintenance of LVEF within the normal range is different to the response seen with deferiprone or combination therapy (deferiprone plus deferoxamine). The exact reason for this difference remains to be elucidated, although one explanation could be the greater access of the small molecule deferiprone to mitochondria, 17 where iron overload may suppress activity of the respiratory chain enzymes involved in the production of ATP. Interestingly, however, an increase in right ventricular ejection fraction measurements was seen with deferasirox, 18 but the relation of this change to the absence of left ventricular functional improvement is not currently understood.…”

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with -thalassemia major

“…6,10 We have previously suggested that one explanation for this difference could be the greater access of deferiprone to mitochondria, 25 where iron overload may suppress activity of the respiratory chain enzymes involved in the production of adenosine triphosphate. 7,25,26 Deferasirox treatment for up to three years appeared to be well tolerated in patients with severe and mild-tomoderate myocardial iron overload. There were no deaths or drug-related serious AEs during 211 patient-years of deferasirox exposure and only one patient reported a serious cardiac AE.…”