title: Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation.
abstract: 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.
authors.affiliation: INSERM U-747 et Université Paris V-Descartes, Centre de Recherche des Saint-Pères, 45 Rue des Saint-Pères, 75006 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Gonzalvez
authors.forename: Marilena
authors.initials: M
authors.lastname: D'Aurelio
authors.forename: Marie
authors.initials: M
authors.lastname: Boutant
authors.forename: Aoula
authors.initials: A
authors.lastname: Moustapha
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Puech
authors.forename: Thomas
authors.initials: T
authors.lastname: Landes
authors.forename: Laeticia
authors.initials: L
authors.lastname: Arnauné-Pelloquin
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.forename: Nellie
authors.initials: N
authors.lastname: Taleux
authors.forename: Christian
authors.initials: C
authors.lastname: Slomianny
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.forename: Pascale
authors.initials: P
authors.lastname: Bellenguer
authors.forename: Ian Max
authors.initials: IM
authors.lastname: Møller
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.forename: Frederic M
authors.initials: FM
authors.lastname: Vaz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Patrice X
authors.initials: PX
authors.lastname: Petit
mesh_terms: D000217:Acyltransferases; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D056889:Barth Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D045222:Electron Transport Chain Complex Proteins; D008246:Lysophospholipids; D014157:Transcription Factors; C067188:monolysocardiolipin; D013481:Superoxides; D000255:Adenosine Triphosphate; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D002950:Citrate (si)-Synthase; D053181:Caspase 8