Petit 2017 MiP2017

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Patrice Petit
Barth syndrome cardiolipin alterations linked to tafazzin mutations lead to apoptosis and mitophygy alterations.

Link: MiP2017

Petit PX (2017)

Event: MiP2017

COST Action MITOEAGLE
Mutations in the gene that encodes the monolyso-transacylase, TAZ, lead to Barth syndrome. Individuals affected by this X-linked multi-system disorder present cardiomyopathy, skeletal muscle weakness, neutropenia, growth retardation and methylglutaconic aciduria (3-MGA). The previous researches on various species models or cells derived from the Barth syndrome have established deep roots laying on top of biochemical characterization of the cellular defects associated to TAZ mutations. Our recent work has focused on basic aspects of the Barth syndrome and also on recent developments into cardiolipin and tafazzin research providing some clues to better understand the link between the Barth syndrome pathology and the mitochondrial dysfunctions exhibiting defects in oxidative phosphorylation, respiratory supercomplexes inorganization, lower ATP production, slight increase oxygen radical production.

We believe that the link between ROS production and sarcomere dysorganization could be straightforward. But, there are some clues linked with autophagic flux destabilization which might be involved in the pathophysiology of the disease. Indeed, after the discovery of inhibition the mitochondrially amplified Fas and TNFα apoptosis[1], we have highlighted a cardiolipin/caspase-8/Bid activation platform at the mitochondrial outer membrane[2] and investigated the occurrence of autophagic processes. The main autophagic processes are unaffected, whereas mitophagy which would have been useful to eliminate the dysfunctionnal mitochondria is totally abolished. Our results are discussed in light of the recent results, especially, the elegant work of Wang’s team[3], that bridges the gap between abnormal ROS production in BTHS derived-iPSCs and the mechanical defect of the sarcomeric structure and function.


Bioblast editor: Kandolf G


Labels: Pathology: Other 







Affiliations

CNRS and INSERM U1124, Univ Paris-Descartes, Centre Univ Saints-Pères, Paris, France. -


References

  1. Gonzalvez F, D'Aurelio M, Boutant M, Moustapha A, Puech JP, Landes T, Arnauné-Pelloquin L, Vial G, Taleux N, Slomianny C, Wanders RJ, Houtkooper RH, Bellenguer P, Møller IM, Gottlieb E, Vaz FM, Manfredi G, Petit PX (2013) Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation BBA 1832:1194-206.
  2. Jalmar O, García-Sáez AJ, Berland L, Gonzalvez F, Petit PX (2010) Giant unilamellar vesicles (GUVs) as a new tool for analysis of caspase-8/Bid-FL complex binding to cardiolipin and its functional activity. Cell Death Dis 1:e103.
  3. Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, Yuan H, Jiang D, Zhang D, Zangi L, Geva J, Roberts AE, Ma Q, Ding J, Chen J, Wang DZ, Li K, Wang J, Wanders RJ, Kulik W, Vaz FM, Laflamme MA, Murry CE, Chien KR, Kelley RI, Church GM, Parker KK, Pu WT (2014) Nat Med 20:616-23.