Blocking phosphatidylglycerol degradation in yeast defective in cardiolipin remodeling results in a new model of the Barth syndrome cellular phenotype

Autor: Paulína Káňovičová, Petra Čermáková, Dominika Kubalová, Lenka Bábelová, Petra Veselá, Martin Valachovič, Jakub Zahumenský, Anton Horváth, Jan Malínský, Mária Balážová
Rok vydání: 2022
Předmět:
WT
wild type
tafazzin
CL
cardiolipin
TAG
triacylglycerols
VPA
valproic acid
Cardiolipins
Pgc1
phosphatidylglycerol phospholipase C
Pgs1
phosphatidylglycerolphosphate synthase
Saccharomyces cerevisiae
PE
phosphatidylethanolamine
PG
phosphatidylglycerol
Biochemistry
Erg1
squalene epoxidase
PI
phosphatidylinositol
ETS capacity
maximum electron transfer system capacity
PC
phosphatidylcholine
valproic acid
BTHS
Barth syndrome
Crd1
cardiolipin synthase
Humans
phosphatidylglycerol
PA
phosphatidic acid
RCI
respiratory control index
Molecular Biology
MLCL
monolysocardiolipin
OXPHOS capacity
oxidative phosphorylation capacity
SE
sterol esters
Taz1
lyso-phosphatidylcholine acyltransferase
Phosphatidylglycerols
Cell Biology
PS
phosphatidylserine
mitochondria
Phenotype
Erg11
lanosterol 14-alpha-demethylase
PGP
phosphatidylglycerol phosphate
Barth Syndrome
lipids (amino acids
peptides
and proteins)
DAG
diacylglycerol
Acyltransferases
Transcription Factors
Research Article
Zdroj: The Journal of Biological Chemistry
ISSN: 0021-9258
Popis: Barth syndrome (BTHS) is an inherited mitochondrial disorder characterized by a decrease in total cardiolipin and the accumulation of its precursor monolysocardiolipin due to the loss of the transacylase enzyme tafazzin. However, the molecular basis of BTHS pathology is still not well understood. Here we characterize the double mutant pgc1Δtaz1Δ of Saccharomyces cerevisiae deficient in phosphatidylglycerol-specific phospholipase C and tafazzin as a new yeast model of BTHS. Unlike the taz1Δ mutant used to date, this model accumulates phosphatidylglycerol, thus better approximating the human BTHS cells. We demonstrate that increased phosphatidylglycerol in this strain leads to more pronounced mitochondrial respiratory defects and an increased incidence of aberrant mitochondria compared to the single taz1Δ mutant. We also show that the mitochondria of the pgc1Δtaz1Δ mutant exhibit a reduced rate of respiration due to decreased cytochrome c oxidase and ATP synthase activities. Finally, we determined that the mood-stabilizing anticonvulsant valproic acid has a positive effect on both lipid composition and mitochondrial function in these yeast BTHS models. Overall, our results show that the pgc1Δtaz1Δ mutant better mimics the cellular phenotype of BTHS patients than taz1Δ cells, both in terms of lipid composition and the degree of disruption of mitochondrial structure and function. This favors the new model for use in future studies.
Databáze: OpenAIRE
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