title: Efficient attenuation of Friedreich's ataxia (FRDA) cardiomyopathy by modulation of iron homeostasis-human induced pluripotent stem cell (hiPSC) as a drug screening platform for FRDA.
abstract: 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.
  
  
  RESULTS
  DFP was able to more significantly suppress synthesis of reactive oxygen species (ROS) than IDE at the dosages of 25 μM and 10nM respectively which agreed with the reduced rate of intracellular accumulation of iron by DFP treatment from 25 to 50 μM. With regard to cardiac electrical-contraction (EC) coupling function, decay velocity of calcium handling kinetics in FRDA-hiPSC-cardiomyocytes was significantly improved by DFP treatment but not by IDE. Further mechanistic studies revealed that DFP also modulated iron induced mitochondrial stress as reflected by mitochondria network disorganization and decline level of respiratory chain protein, succinate dehydrogenase (CxII) and cytochrome c oxidase (COXIV). In addition, iron-response protein (IRP-1) regulatory loop was overridden by DFP as reflected by resumed level of ferritin (FTH) back to basal level and the attenuated transferrin receptor (TSFR) mRNA level suppression thereby reducing further iron uptake.
  
  
  CONCLUSIONS
  DFP modulated iron homeostasis in FRDA-hiPSC-cardiomyocytes and effectively relieved stress-stimulation related to cardiomyopathy. The resuming of redox condition led to the significantly improved cardiac prime events, cardiac electrical-coupling during contraction.
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yee-Ki
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yee-Man
authors.initials: YM
authors.lastname: Lau
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Kwong-Man
authors.initials: KM
authors.lastname: Ng
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Wing-Hon
authors.initials: WH
authors.lastname: Lai
authors.affiliation: Neurology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Shu-Leong
authors.initials: SL
authors.lastname: Ho
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, China; Hong Kong - Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chung-Wah
authors.initials: CW
authors.lastname: Siu
authors.affiliation: Neurology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: hwl2002@hku.hk.
authors.forename: Philip Wing-Lok
authors.initials: PW
authors.lastname: Ho
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D000077543:Deferiprone; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D033862:Iron-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D011728:Pyridones / Q000494:pharmacology*; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000096923:Frataxin
chemical_list: D000975:Antioxidants; D000077543:Deferiprone; D007501:Iron; D007502:Iron Chelating Agents; D033862:Iron-Binding Proteins; D011728:Pyridones; D012313:RNA; D014451:Ubiquinone; D000096923:Frataxin; C036619:idebenone
keywords: Cardiomyopathy; Deferiprone; Friedreich's ataxia; Idebenone; Induced pluripotent stem cells