Decreasing cytosolic translation is beneficial to yeast and human Tafazzin-deficient cells

Authors:

Maxence de Taffin de Tilques1,$, Jean-Paul Lasserre1,$, François Godard1, Elodie Sardin1, Marine Bouhier1, Marina Le Guedard2,3, Roza Kucharczyk4, Patrice X. Petit5, Eric Testet2, Jean-Paul di Rago1, Déborah Tribouillard-Tanvier1,#

doi: 10.15698/mic2018.05.629
Volume 5, pp. 220 to 232, published 18/02/2018.

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Affiliations:

1 Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, 1 rue Camille Saint-Saëns, 33077 Bordeaux cedex, France.

2 Laboratoire de Biogenèse Membranaire, CNRS UMR 5200, Université de Bordeaux, INRA Bordeaux Aquitaine, Villenave d’Ornon, France.

3 LEB Aquitaine Transfert-ADERA, FR-33883 Villenave d’Ornon, Cedex, France.

4 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

5 CNRS FR3636 Fédération de recherché en Neuroscience, Université Paris-Descartes, 45, rue des Saints-Pères, 75006 Paris, France.

# Research associate from INSERM.

$ These authors contributed equally.

Keywords: 

mitochondrial disease, oxidative phosphorylation, Barth syndrome, cytosolic protein synthesis, cycloheximide; cardiolipin remodeling

Corresponding Author(s):

Déborah Tribouillard-Tanvier, Phone: +33 5 56 99 90 39, Fax: +33 5 56 99 90 51; deborah.tribouillard-tanvier@ibgc.cnrs.fr Jean-Paul Lasserre, Phone: +33 5 56 99 90 39, Fax: +33 5 56 99 90 51; jean-paul.lasserre@ibgc.cnrs.fr

Conflict of interest statement:

The authors declare no competing or financial interests.

Please cite this article as:

Maxence de Taffin de Tilques, Jean-Paul Lasserre, François Godard, Elodie Sardin, Marine Bouhier, Marina Le Guedard, Roza Kucharczyk, Patrice X. Petit, Eric Testet, Jean-Paul di Rago, Déborah Tribouillard-Tanvier (2018). Decreasing cytosolic translation is beneficial to yeast and human Tafazzin-deficient cells. Microbial Cell 5(5): 220-232. doi: 10.15698/mic2018.05.629

© 2018 de Taffin de Tilques et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

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.