Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation

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  • François Gonzalvez, INSERM U-747 et Université Paris V-Descartes, Centre de Recherche des Saint-Pères, 45 Rue des Saint-Pères, 75006 Paris, France.
  • ,
  • Marilena D'Aurelio
  • ,
  • Marie Boutant, INSERM U-747 et Université Paris V-Descartes, Centre de Recherche des Saint-Pères, France
  • Aoula Moustapha, INSERM U-747 et Université Paris V-Descartes, Centre de Recherche des Saint-Pères, France
  • Jean-Philippe Puech, INSERM U-747 et Université Paris V-Descartes, Centre de Recherche des Saint-Pères, France
  • Thomas Landes, Université de Toulouse, Centre de Biologie du Développement, CNRS UMR5547/Université Paul Sabatier, France
  • Laeticia Arnauné-Pelloquin, Université de Toulouse, Centre de Biologie du Développement, CNRS UMR5547/Université Paul Sabatier, France
  • Guillaume Vial, Laboratoire de Bioénergétique Fondamentale et Appliquée, LBFA-INSERM U884, Université J. Fourier, France
  • Nellie Taleux, Laboratoire de Bioénergétique Fondamentale et Appliquée, LBFA-INSERM U884, Université J. Fourier, France
  • Christian Slomianny, Laboratoire de Physiologie cellulaire, INSERM U800, Université des Sciences et Techniques de Lille 1, France
  • Ronald J Wanders, Department of Clinical Chemistry and Department of Pediatrics, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, Netherlands
  • Riekelt H Houtkooper, Department of Clinical Chemistry and Department of Pediatrics, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Netherlands
  • Pascale Bellenguer, Université de Toulouse, Centre de Biologie du Développement, CNRS UMR5547/Université Paul Sabatier, France
  • Ian Max Møller
  • Eyal Gottlieb, Department of Clinical Chemistry and Department of Pediatrics, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, Netherlands
  • Frederic M Vaz, Department of Clinical Chemistry and Department of Pediatrics, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Netherlands
  • Giovanni Manfredi, Weill Medical College of Cornell University, United States
  • Patrice X Petit, INSERM U-747 et Université Paris V-Descartes, Centre de Recherche des Saint-Pères, France
Cardiolipin is a mitochondrion-specific phospholipid that stabilizes the assembly of respiratory chain complexes, favoring full-yield operation. It also mediates key steps in apoptosis. In Barth syndrome, an X chromosome-linked cardiomyopathy caused by tafazzin mutations, cardiolipins display acyl chain modifications and are present at abnormally low concentrations, whereas monolysocardiolipin accumulates. Using immortalized lymphoblasts from Barth syndrome patients, we showed that the production of abnormal cardiolipin led to mitochondrial alterations. Indeed, the lack of normal cardiolipin led to changes in electron transport chain stability, resulting in cellular defects. We found a destabilization of the supercomplex (respirasome) I+III2+IVn but also decreased amounts of individual complexes I and IV and supercomplexes I+III and III+IV. No changes were observed in the amounts of individual complex III and complex II. We also found decreased levels of complex V. This complex is not part of the supercomplex suggesting that cardiolipin is required not only for the association/stabilization of the complexes into supercomplexes but also for the modulation of the amount of individual respiratory chain complexes. However, these alterations were compensated by an increase in mitochondrial mass, as demonstrated by electron microscopy and measurements of citrate synthase activity. We suggest that this compensatory increase in mitochondrial content prevents a decrease in mitochondrial respiration and ATP synthesis in the cells. We also show, by extensive flow cytometry analysis, that the type II apoptosis pathway was blocked at the mitochondrial level and that the mitochondria of patients with Barth syndrome cannot bind active caspase-8. Signal transduction is thus blocked before any mitochondrial event can occur. Remarkably, basal levels of superoxide anion production were slightly higher in patients' cells than in control cells as previously evidenced via an increased protein carbonylation in the taz1Δ mutant in the yeast. This may be deleterious to cells in the long term. The consequences of mitochondrial dysfunction and alterations to apoptosis signal transduction are considered in light of the potential for the development of future treatments.
Original languageEnglish
JournalB B A - Molecular Basis of Disease
Volume1832
Issue8
Pages (from-to)1194-1206
Number of pages13
ISSN0925-4439
DOIs
Publication statusPublished - Aug 2013

    Research areas

  • Adenosine Triphosphate, Apoptosis, Barth Syndrome, Cardiolipins, Caspase 8, Cell Death, Cell Line, Citrate (si)-Synthase, Electron Transport Chain Complex Proteins, Humans, Lymphocytes, Lysophospholipids, Mitochondria, Mutation, Signal Transduction, Superoxides, Transcription Factors

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