title: A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model.
abstract: Friedreich's ataxia (FRDA) is the most common inherited human ataxia and results from a deficiency of the mitochondrial protein, frataxin (FXN), which is encoded in the nucleus. This deficiency is associated with an iron-sulfur (Fe-S) cluster enzyme deficit leading to progressive ataxia and a frequently fatal cardiomyopathy. There is no cure. To determine whether exogenous replacement of the missing FXN protein in mitochondria would repair the defect, we used the transactivator of transcription (TAT) protein transduction domain to deliver human FXN protein to mitochondria in both cultured patient cells and a severe mouse model of FRDA. A TAT-FXN fusion protein bound iron in vitro, transduced into mitochondria of FRDA deficient fibroblasts and reduced caspase-3 activation in response to an exogenous iron-oxidant stress. Injection of TAT-FXN protein into mice with a conditional loss of FXN increased their growth velocity and mean lifespan by 53% increased their mean heart rate and cardiac output, increased activity of aconitase and reversed abnormal mitochondrial proliferation and ultrastructure in heart. These results show that a cell-penetrant peptide is capable of delivering a functional mitochondrial protein in vivo to rescue a very severe disease phenotype, and present the possibility of TAT-FXN as a protein replacement therapy.
authors: Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Piyush M
authors: PM
authors: Vyas
authors: Wendy J
authors: WJ
authors: Tomamichel
authors: P Melanie
authors: PM
authors: Pride
authors: Clifford M
authors: CM
authors: Babbey
authors: Qiujuan
authors: Q
authors: Wang
authors: Jennifer
authors: J
authors: Mercier
authors: Elizabeth M
authors: EM
authors: Martin
authors: R Mark
authors: RM
authors: Payne
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005621:Friedreich Ataxia / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D015696:Gene Products, tat / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D053148:Caspase 3; D015696:Gene Products, tat; D019426:Integrases; D007501:Iron; D033862:Iron-Binding Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000096923:Frataxin; C045073:Cre recombinase