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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Gonzalvez, Francois^1,2,3,11  D'Aurelio, Marilena⁴  Boutant, Marie^1,2  Moustapha, Aoula^1,2  Puech, Jean-Philippe^1,2  Landes, Thomas⁵  Arnaune-Pelloquin, Laeticia⁵  Vial, Guillaume⁶  Taleux, Nellie⁶  Slomianny, Christian⁷  Wanders, Ronald J.^8,9  Houtkooper, Riekelt H.^8,9  Bellenguer, Pascale⁵  Moller, Ian Max¹⁰  Gottlieb, Eyal¹¹  Vaz, Frederic M.^8,9  Manfredi, Giovanni⁴  Petit, Patrice X.^1,2 

[1] INSERM U747, F-75006 Paris, France

[2] Univ Paris 05, Ctr Rech St Peres, F-75006 Paris, France

[3] Genentech Inc, San Francisco, CA 94080 USA

[4] Cornell Univ, Weill Med Coll, New York, NY 10021 USA

[5] Univ Toulouse 3, Univ Toulouse, Ctr Biol Dev, CNRS UMR5547, F-31062 Toulouse, France

[6] Univ Grenoble 1, LBFA, INSERM U884, F-38041 Grenoble 9, France

[7] Univ Sci & Tech Lille 1, Lab Physiol Cellulaire, INSERM U800, F-59655 Villeneuve Dascq, France

[8] Univ Amsterdam, Acad Med Ctr, Dept Clin Chem, NL-1105 AZ Amsterdam, Netherlands

[9] Univ Amsterdam, Acad Med Ctr, Dept Pediat, Lab Genet Metab Dis, NL-1105 AZ Amsterdam, Netherlands

[10] Aarhus Univ, Dept Mol Biol & Genet Sci & Technol, DK-4200 Slagelse, Denmark

[11] Beatson Inst Canc Res, Canc Res UK, Glasgow G61 1BD, Lanark, Scotland

关键词: Apoptosis;    Barth syndrome;    Cardiolipin;    Mitochondria;    Reactive oxygen species;    Respiratory complex;   

DOI  :  10.1016/j.bbadis.2013.03.005

来源: Elsevier

【 摘 要 】

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 taz1 Delta 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. (C) 2013 Elsevier B.V. All rights reserved.

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