title: Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism.
abstract: 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. Using this approach, frataxin was reduced down to 5 to 30% of control protein levels after 7 days of transduction. At this stage the activity and amount of the iron-sulfur protein aconitase, in vitro activities of several OXPHOS components, levels of iron-regulated mRNAs, and the ATP/ADP ratio were comparable to controls. However, NRVMs exhibited markers of oxidative stress and a disorganized mitochondrial network with enlarged mitochondria. Lipids, the main energy source of heart cells, also underwent a clear metabolic change, indicated by the increased presence of lipid droplets and induction of medium-chain acyl-CoA dehydrogenase. These results indicate that mitochondria and lipid metabolism are primary targets of frataxin deficiency in NRVMs. Therefore, they contribute to the understanding of cardiac-specific mechanisms occurring in FRDA and give clues for the design of cardiac-specific treatment strategies for FRDA.
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, 25198 Lleida, Spain.
authors.forename: Èlia
authors.initials: È
authors.lastname: Obis
authors.affiliation: Instituto de Investigación para la Industria Química, INIQUI-CONICET, Salta, Argentina.
authors.forename: Verónica
authors.initials: V
authors.lastname: Irazusta
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, 25198 Lleida, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sanchís
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, 25198 Lleida, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ros
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, 25198 Lleida, Spain. Electronic address: jordi.tamarit@cmb.udl.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Tamarit
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005621:Friedreich Ataxia / Q000473:pathology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D033862:Iron-Binding Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D034741:RNA, Small Interfering; D000096923:Frataxin
keywords: Free radicals; Friedreich ataxia; Iron; Lipid metabolism; Mitochondria; Oxidative stress