The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

Abstract

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MITpermeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.ferritin ͉ iron chelators ͉ mitochondria ͉ transferrin receptor ͉ frataxin

Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant

“…Tfr1, the primary source of iron uptake (28), was significantly (P Ͻ .01) increased at the mRNA and protein levels in the 4-week-old mutants and especially in the 10-week-old mutants. Both upregulation of Tfr1 and down-regulation of Fpn1 are consistent with our previous findings using MCK mutants (11). These observations suggest increased iron import and decreased iron export, respectively, and are indicative of a response to cytosolic iron deficiency.…”

“…This increase in mitochondrial iron trafficking would exacerbate the cytosolic iron deficiency and facilitate mitochondrial iron overload. This could lead to a constant iron flux being trafficked to the mitochondrion, where iron utilization pathways are down-regulated (see below), leading to mitochondrial iron accumulation (7,11).…”

“…Our aim was to explore the changes in iron metabolism due to frataxin deficiency. These mutants exhibit classical traits of the cardiomyopathy in Friedreich's ataxia, including cardiac hypertrophy, ISC enzyme deficiency, and marked mitochondrial iron accumulation (7,11,24). Thus, this model closely reflects the cardiac pathology in Friedreich's ataxia.…”

“…Frataxin depletion results in mitochondrial DNA damage, mitochondrial iron accumulation, ISC deficiency, perturbed heme synthesis, and oxidative damage (6)(7)(8)(9). In addition, recent studies have suggested cytosolic iron deficiency in Friedreich's ataxia models, as indicated by increased RNA-binding activity of iron regulatory protein 2, increased expression of transferrin receptor 1 (Tfr1), and decreased cytosolic ferritin (10,11).…”

“…compared with WT littermates. We compared gene expression in the mutant and WT littermates at age 4 weeks, when no overt phenotype is evident, and at age 10 weeks, when cardiomyopathy is evident, including marked mitochondrial iron loading (7,11).…”