Journal
MICROBIAL CELL
Volume 5, Issue 5, Pages 220-232Publisher
SHARED SCIENCE PUBLISHERS OG
DOI: 10.15698/mic2018.05.629
Keywords
mitochondrial disease; oxidative phosphorylation; Barth syndrome; cytosolic protein synthesis; cycloheximide; cardiolipin remodeling
Categories
Funding
- Association Frangaise contre les Myopathies (AFM)
- Barth Syndrome Foundation (BSF), Association Barth France
- Association contre les Maladies Mitochondriales (AMMI)
- French Ministere de l'Enseignement et de la Recherche
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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-offunction 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 (taz1 Delta). Interestingly, the defaults in CL were not suppressed, indicating that they are not primarily responsible for the OXPHOS deficiency in taz1 Delta 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.
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