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

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.

ReporterSeq reveals genome-wide dynamic modulators of the heat shock response across diverse stressors

“…For example, a major mystery is how genes regulating translation and mitochondria, which showed strong interactions with multiple conditions, regulate the HSR. Additionally, how the Ras/cAMP pathway and Taz1, which has been proposed to be essential for protein homeostasis ( de Taffin de Tilques et al, 2018 ), regulate the HSR is poorly understood. Interaction data from our ReporterSeq experiments may be useful in formulating hypotheses that can be tested with detailed follow-up experiments.…”

Mitochondrial stress-dependent regulation of cellular protein synthesis

“…Deletion of taffazin was accompanied by an increase in ROS levels (Chen et al, 2008) and a partial decrease in cytosolic translation (de Taffin de Tilques et al, 2018). Interestingly, further mild inhibition of translation by chemical inhibition restored OXPHOS function and cell proliferation (de Taffin de Tilques et al, 2018). This suggests that a certain threshold of lower cytosolic translation must be reached to activate the recovery response.…”

“…Further supporting selective protein production upon an increase in ROS levels was an analysis of deletion of the taffazin gene (Taz1 in yeast), which caused defects in mitochondrial OXPHOS (de Taffin de Tilques et al, 2018). Deletion of taffazin was accompanied by an increase in ROS levels (Chen et al, 2008) and a partial decrease in cytosolic translation (de Taffin de Tilques et al, 2018). Interestingly, further mild inhibition of translation by chemical inhibition restored OXPHOS function and cell proliferation (de Taffin de Tilques et al, 2018).…”

Mitochondrial Genome Variation Affects Multiple Respiration and Nonrespiration Phenotypes in Saccharomyces cerevisiae

“…Alternatively, there is a nonretrograde signaling hypothesis for mitochondrial genotype-dependent cycloheximide resistance. The cytosolic translation inhibitor cycloheximide has been shown to rescue some nuclear mutations that cause mitochondrial dysfunction, possibly by reducing the toxic cytosolic accumulation of nuclearly encoded, mitochondrially targeted proteins (Wang et al 2008;Wang and Chen 2015;Wrobel et al 2015;de Taffin de Tilques et al 2018;Guaragnella et al 2018). Thus, epistatic nuclear-mitochondrial genotype interactions in some r+ iso-nuclear F1 pairs may result in cycloheximide-remediable mitochondrial dysfunction in one of the iso-nuclear F1, and consequently, mitochondrial genotype-dependent cycloheximide resistance.…”