Petit 2018 MiP2018
Cardiolipin (CL) optimizes diverse mitochondrial processes, including oxidative phosphorylation (OXPHOS). To function properly, CL needs to be unsaturated, which requires the acyltransferase Tafazzin (TAZ).
Loss-of-function mutations in the TAZ gene are responsible for the Barth syndrome (BTHS), a rare X-linked cardiomyopathy, presumably because of a diminished OXPHOS capacity . Herein we show that a partial inhibition of cytosolic protein synthesis, either chemically with the use of cycloheximide or by specific genetic mutations, fully restores biogenesis and the activity of the oxidative phosphorylation system in a yeast BTHS model (taz1Δ). Interestingly, the defaults in CL were not suppressed, indicating that they are not primarily responsible for the OXPHOS deficiency in taz1Δ yeast.
Low concentrations of cycloheximide in the picomolar range were beneficial to TAZ-deficient HeLa cells, as evidenced by the recovery of a good proliferative capacity. These findings reveal that a diminished capacity of CL remodeling deficient cells to preserve protein homeostasis is likely an important factor contributing to the pathogenesis of BTHS. This in turn, identifies cytosolic translation as a potential therapeutic target for the treatment of this disease.
Labels: MiParea: mt-Biogenesis;mt-density, nDNA;cell genetics Pathology: Myopathy
Organism: Human, Saccharomyces cerevisiae Tissue;cell: HeLa
De Taffin de Tilques M(2), Lasserre JP(2), Godard F, Sardin E, Bouhier M, Le Guedard M, Kucharczyk R, Testet E, Di Rago JP(2), Tribouillard-Tanvier D(2), Petit PX(1)
- CNRS FR3636, Inst de Neurosciences, Univ Paris-Descartes
- Inst de Biochimie et génétique cellulaire, CNRS UMR 5095, Univ de Bordeaux; France. - [email protected]
- Saric A, Andreau K, Armand AS, Møller IM, Petit PX (2016) Barth Syndrome: from mitochondrial dysfunctions associated with aberrant production of reactive oxygen species to pluripotent stem cell studies. Front Genet 6:359.
- 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. Biochim Biophys Acta 1832:1194-206.
- de Taffin de Tilques M, Lasserre JP, Godard F, Sardin E, Bouhier M, Le Guedard M, Kucharczyk R, Petit PX, Testet E, di Rago JP, Tribouillard-Tanvier D (2018) Decreasing cytosolic translation is beneficial to yeast and human Tafazzin-deficient cells. Microb Cell 5:220–32.