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Frataxin and cardiomyocytes

Rosella Abeti, Alexander F Brown, Marta Maiolino, Sandip Patel, Paola Giunti
Friedreich's Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes of FRDA cellular models to understand the pathogenesis of degeneration...
2018: Frontiers in Cellular Neuroscience
Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier
Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions...
July 20, 2018: Disease Models & Mechanisms
R Purroy, E Britti, F Delaspre, J Tamarit, J Ros
Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons...
February 2018: Biochimica et biophysica acta. Molecular basis of disease
Duncan E Crombie, Claire L Curl, Antonia Ja Raaijmakers, Priyadharshini Sivakumaran, Tejal Kulkarni, Raymond Cb Wong, Itsunari Minami, Marguerite V Evans-Galea, Shiang Y Lim, Lea Delbridge, Louise A Corben, Mirella Dottori, Norio Nakatsuji, Ian A Trounce, Alex W Hewitt, Martin B Delatycki, Martin F Pera, Alice Pébay
We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes...
May 30, 2017: Aging
Arnulf H Koeppen, Alyssa B Becker, Paul J Feustel, Benjamin B Gelman, Joseph E Mazurkiewicz
Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling...
August 15, 2016: Journal of the Neurological Sciences
Shota Sasagawa, Yuhei Nishimura, Shiko Okabe, Soichiro Murakami, Yoshifumi Ashikawa, Mizuki Yuge, Koki Kawaguchi, Reiko Kawase, Ryuji Okamoto, Masaaki Ito, Toshio Tanaka
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and is associated with a number of potential outcomes, including impaired diastolic function, heart failure, and sudden cardiac death. Various etiologies have been described for HCM, including pressure overload and mutations in sarcomeric and non-sarcomeric genes. However, the molecular pathogenesis of HCM remains incompletely understood. In this study, we performed comparative transcriptome analysis to identify dysregulated genes common to five mouse HCM models of differing etiology: (i) mutation of myosin heavy chain 6, (ii) mutation of tropomyosin 1, (iii) expressing human phospholamban on a null background, (iv) knockout of frataxin, and (v) transverse aortic constriction...
2016: Frontiers in Pharmacology
Yee-Ki Lee, Yee-Man Lau, Kwong-Man Ng, Wing-Hon Lai, Shu-Leong Ho, Hung-Fat Tse, Chung-Wah Siu, Philip Wing-Lok Ho
BACKGROUND: Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is caused by silencing of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron-sulfur cluster biosynthesis. METHODS: Application of our previously established FRDA human induced pluripotent stem cell (hiPSC) derived cardiomyocytes model as a platform to assess the efficacy of treatment with either the antioxidant coenzyme Q10 analog, idebenone (IDE) or the iron chelator, deferiprone (DFP), which are both under clinical trial...
January 15, 2016: International Journal of Cardiology
Gayani Nanayakkara, Abdullah Alasmari, Shravanthi Mouli, Haitham Eldoumani, John Quindry, Graham McGinnis, Xiaoyu Fu, Avery Berlin, Bridget Peters, Juming Zhong, Rajesh Amin
Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 α against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1α against I/R injury exerted via the mitochondrial protein frataxin, which regulates mitochondrial Fe-S cluster formation. Disruption of frataxin has been found to induce mitochondrial iron overload and subsequent ROS production. We observed that frataxin expression was elevated in mice hearts subjected to I/R injury, and this response was blunted in cardiomyocyte-specific HIF-1α knockout (KO) mice...
September 2015: American Journal of Physiology. Heart and Circulatory Physiology
Arnulf H Koeppen, R Liane Ramirez, Alyssa B Becker, Sarah T Bjork, Sonia Levi, Paolo Santambrogio, Patrick J Parsons, Pamela C Kruger, Karl X Yang, Paul J Feustel, Joseph E Mazurkiewicz
Friedreich ataxia (FA) is an autosomal recessive disease with a complex neurological phenotype, but the most common cause of death is heart failure. This study presents a systematic analysis of 15 fixed and 13 frozen archival autopsy tissues of FA hearts and 10 normal controls (8 frozen) by measurement of cardiomyocyte hypertrophy; tissue frataxin assay; X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn) in polyethylene glycol-embedded samples of left and right ventricular walls (LVW, RVW) and ventricular septum (VS); metal quantification in bulk digests by inductively-coupled plasma optical emission spectrometry (ICP-OES); Fe histochemistry; and immunohistochemistry and immunofluorescence of cytosolic and mitochondrial ferritins and of the inflammatory markers CD68 and hepcidin...
2015: PloS One
Naoki Tajiri, Meaghan Staples, Yuji Kaneko, Seung U Kim, Theresa A Zesiewicz, Cesar V Borlongan
We advance the overarching hypothesis that stem cell therapy is a potent treatment for Friedreich's ataxia (FRDA). Here, we discuss the feasibility of autologous transplantation in FRDA, highlighting the need for the successful isolation of the FRDA patient's bone marrow-derived mesenchymal stem cells, followed by characterization that these cells maintain the GAA repeat expansion and the reduced FXN mRNA expression, both hallmark features of FRDA. Next, we discuss the need for assessment of the proliferative capability and pluripotency of FRDA patient's bone marrow-derived mesenchymal stem cells...
September 2014: Medical Hypotheses
H Puccio, M Anheim, C Tranchant
Friedreich ataxia (FRDA) is the most common hereditary autosomal recessive ataxia, but is also a multisystemic condition with frequent presence of cardiomyopathy or diabetes. It has been linked to expansion of a GAA-triplet repeat in the first intron of the FXN gene, leading to a reduced level of frataxin, a mitochondrial protein which, by controlling both iron entry and/or sulfide production, is essential to properly assemble and protect the Fe-S cluster during the initial stage of biogenesis. Several data emphasize the role of oxidative damage in FRDA, but better understanding of pathophysiological consequences of FXN mutations has led to develop animal models...
May 2014: Revue Neurologique
Èlia Obis, Verónica Irazusta, Daniel Sanchís, Joaquim Ros, Jordi Tamarit
Friedreich ataxia (FRDA) is a hereditary disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Patients with FRDA experience neurologic alterations and cardiomyopathy, which is the leading cause of death. The specific effects of frataxin depletion on cardiomyocytes are poorly understood because no appropriate cardiac cellular model is available to researchers. To address this research need, we present a model based on primary cultures of neonatal rat ventricular myocytes (NRVMs) and short-hairpin RNA interference...
August 2014: Free Radical Biology & Medicine
Morgane Perdomini, Brahim Belbellaa, Laurent Monassier, Laurence Reutenauer, Nadia Messaddeq, Nathalie Cartier, Ronald G Crystal, Patrick Aubourg, Hélène Puccio
Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA...
May 2014: Nature Medicine
Yee-Ki Lee, Philip Wing-Lok Ho, Revital Schick, Yee-Man Lau, Wing-Hon Lai, Ting Zhou, Yanhua Li, Kwong-Man Ng, Shu-Leung Ho, Miguel Angel Esteban, Ofer Binah, Hung-Fat Tse, Chung-Wah Siu
Friedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron-sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force...
September 2014: Pflügers Archiv: European Journal of Physiology
Caterina Mariotti, Wolfgang Nachbauer, Marta Panzeri, Werner Poewe, Franco Taroni, Sylvia Boesch
In Friedreich ataxia (FRDA), several candidate substances including erythropoietin (EPO) focus on increase in the amount of frataxin and aim to counteract the consequences of frataxin deficiency. Evidence for recombinant human erythropoietin (rHuEPO) in FRDA is based on in vitro studies using mouse neuronal cell lines, human fibroblasts, cardiomyocytes, and primary lymphocytes from FRDA patients or control subjects which showed a dose-dependent increase of frataxin after incubation with different erythropoietins...
August 2013: Journal of Neurochemistry
Darius J R Lane, Michael Li-Hsuan Huang, Samantha Ting, Sutharshani Sivagurunathan, Des R Richardson
FRDA (Friedreich's ataxia) is a debilitating mitochondrial disorder leading to neural and cardiac degeneration, which is caused by a mutation in the frataxin gene that leads to decreased frataxin expression. The most common cause of death in FRDA patients is heart failure, although it is not known how the deficiency in frataxin potentiates the observed cardiomyopathy. The major proposed biochemical mechanisms for disease pathogenesis and the origins of heart failure in FRDA involve metabolic perturbations caused by decreased frataxin expression...
August 1, 2013: Biochemical Journal
Aurore Hick, Marie Wattenhofer-Donzé, Satyan Chintawar, Philippe Tropel, Jodie P Simard, Nadège Vaucamps, David Gall, Laurie Lambot, Cécile André, Laurence Reutenauer, Myriam Rai, Marius Teletin, Nadia Messaddeq, Serge N Schiffmann, Stéphane Viville, Christopher E Pearson, Massimo Pandolfo, Hélène Puccio
Friedreich's ataxia (FRDA) is a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy. FRDA is due to expanded GAA repeats within the first intron of the gene encoding frataxin, a conserved mitochondrial protein involved in iron-sulphur cluster biosynthesis. This mutation leads to partial gene silencing and substantial reduction of the frataxin level. To overcome limitations of current cellular models of FRDA, we derived induced pluripotent stem cells (iPSCs) from two FRDA patients and successfully differentiated them into neurons and cardiomyocytes, two affected cell types in FRDA...
May 2013: Disease Models & Mechanisms
R Liane Ramirez, Jiang Qian, Paolo Santambrogio, Sonia Levi, Arnulf H Koeppen
Cardiomyopathy is the leading cause of death in Friedreich's ataxia. This autosomal recessive disease is caused by a homozygous guanine-adenine-adenine trinucleotide repeat expansion in the frataxin gene (chromosome 9q21). One untoward effect of frataxin deficiency is the lack of iron (Fe)-sulfur clusters. Progressive remodeling of the heart in FA, however, 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...
December 15, 2012: American Journal of Cardiology
Jun Liu, Paul J Verma, Marguerite V Evans-Galea, Martin B Delatycki, Anna Michalska, Jessie Leung, Duncan Crombie, Joseph P Sarsero, Robert Williamson, Mirella Dottori, Alice Pébay
Friedreich ataxia (FRDA) is an autosomal recessive disorder characterised by neurodegeneration and cardiomyopathy. It is caused by a trinucleotide (GAA) repeat expansion in the first intron of the FXN gene that results in reduced synthesis of FXN mRNA and its protein product, frataxin. We report the generation of induced pluripotent stem (iPS) cell lines derived from skin fibroblasts from two FRDA patients. Each of the patient-derived iPS (FA-iPS) cell lines maintain the GAA repeat expansion and the reduced FXN mRNA expression that are characteristic of the patient...
September 2011: Stem Cell Reviews
Mary A Selak, Elise Lyver, Elizabeth Micklow, Eric C Deutsch, Ozlem Onder, Nur Selamoglu, Claire Yager, Simon Knight, Martin Carroll, Fevzi Daldal, Andrew Dancis, David R Lynch, Jean-Emmanuel Sarry
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by GAA triplet expansions or point mutations in the FXN gene on chromosome 9q13. The gene product called frataxin, a mitochondrial protein that is severely reduced in FRDA patients, leads to mitochondrial iron accumulation, Fe-S cluster deficiency and oxidative damage. The tissue specificity of this mitochondrial disease is complex and poorly understood. While frataxin is ubiquitously expressed, the cellular phenotype is most severe in neurons and cardiomyocytes...
March 2011: Mitochondrion
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