Cardiomyopathy of Friedreich’s Ataxia: Use of Mouse Models to Understand Human Disease and Guide Therapeutic Development

Payne, R. Mark; Pride, P. Melanie; Babbey, Clifford M.

doi:10.1007/s00246-011-9943-6

Cited by 23 publications

(22 citation statements)

References 90 publications

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“…The main problem in FA remains deficiency of mitochondrial frataxin, and cardiomyocytes may become vulnerable by mechanisms not directly related to Fe. In support of apoptosis, caspase-3 immunostaining shows an excess of immunoreactive cardiomyocytes in the MCK mouse 23 .…”

Section: Discussionmentioning

confidence: 88%

Relation of Cytosolic Iron Excess to Cardiomyopathy of Friedreich's Ataxia

Ramirez

Jiang

Santambrogio

et al. 2012

The American Journal of Cardiology

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Cardiomyopathy is the leading cause of death in Friedreich's ataxia (FA). This autosomal recessive disease is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in the frataxin gene (chromosome 9q21). One untoward effect of frataxin deficiency is lack of iron (Fe)-sulfur clusters, but progressive remodeling of the heart in FA may be more specifically related to sarcoplasmic Fe overload. The Fe-containing inclusions in a small percentage of cardiomyocytes may not represent purely mitochondrial accumulation of the metal. The objective of this work was to re-examine the contribution of Fe to cardiomyocyte hypertrophy, fiber necrosis, and myocardial scarring by a combination of X-ray fluorescence (XRF), slide histochemistry of Fe, and immunohistochemistry of two Fe-related proteins. Polyethyleneglycol (PEG)-embedded human cardiac tissues from left and right ventricular walls; ventricular septum; right atrium; and atrial septum were studied by qualitative and quantitative XRF. Tissues were recovered from the PEG matrix, re-embedded in paraffin, and sectioned for the visualization of Fe, ferritin, and ferroportin. XRF showed quantifiable levels of Fe and zinc (Zn). Regions of significantly increased Fe (1–4 mm2) were irregularly distributed throughout the working myocardium. Fe granules were sparse in conductive tissue. Zn signals remained unchanged. Robust cytosolic ferritin reaction product occurred in many fibers of the affected regions. Ferroportin displayed no response except in fibers with advanced Fe overload. These observations are at variance with the concept of selective Fe overload only in cardiac mitochondria. Fe-mediated damage to cardiomyocytes and myocardial scarring are more likely due to cytosolic Fe excess.

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Section: Discussionmentioning

confidence: 88%

Relation of Cytosolic Iron Excess to Cardiomyopathy of Friedreich's Ataxia

Ramirez

Jiang

Santambrogio

et al. 2012

The American Journal of Cardiology

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“…Puccio et al (58) generated a dramatic cardiac phenotype by deleting exon 4 of the murine fxn gene and targeting the deletion to striated muscle through the muscle creatine kinase promoter. This model is being used in the study of FRDA-like cardiomyopathy (50, 59), but a comparable approach to the nervous system by involving the neuron-specific enolase promoter spared DRG. Peculiarly, the cerebral cortex and peripheral sensory nerve were affected (58).…”

Section: Pathogenesis Of Frdamentioning

confidence: 99%

Friedreich Ataxia: Neuropathology Revised

Koeppen

Mazurkiewicz

2013

J Neuropathol Exp Neurol

217

233

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Friedreich ataxia is an autosomal recessive disorder that affects children and young adults. The mutation consists of a homozygous guanine-adenine-adenine trinucleotide repeat expansion that causes deficiency of frataxin, a small nuclear genome–encoded mitochondrial protein. Low frataxin levels lead to insufficient biosynthesis of iron-sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase, and iron dysmetabolism of the entire cell. This review of the neuropathology of Friedreich ataxia stresses the critical role of hypoplasia and superimposed atrophy of dorsal root ganglia. Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal columns, transsynaptic atrophy of nerve cells in Clarke column and dorsal spinocerebellar fibers, atrophy of gracile and cuneate nuclei, and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain γ-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second intrinsic CNS lesion. In light of the selective vulnerability of organs and tissues to systemic frataxin deficiency, many questions about the pathogenesis of Friedreich ataxia remain.

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“…The deficit in transcription of FXN in FRDA patients is often characterized by mitochondrial damage and the ensuing energy dysregulation (17,41). The central pathological outcomes of FRDA on the heart include hypertrophic cardiomyopathy, myocardial fibrosis, and myocardial infarction, which often progress the heart to congestive heart failure (38,39,53).…”

Section: New and Noteworthymentioning

confidence: 99%

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Mouli

Nanayakkara

AlAlasmari

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

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Cardiomyopathy of Friedreich’s Ataxia: Use of Mouse Models to Understand Human Disease and Guide Therapeutic Development

Cited by 23 publications

References 90 publications

Relation of Cytosolic Iron Excess to Cardiomyopathy of Friedreich's Ataxia

Relation of Cytosolic Iron Excess to Cardiomyopathy of Friedreich's Ataxia

Friedreich Ataxia: Neuropathology Revised

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

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