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

0567212 - ÚEM 2023 RIV US eng J - Journal Article
Káňovičová, P. - Čermáková, P. - Kubalová, D. - Bábelová, A. - Veselá, Petra - Valachovič, M. - Zahumenský, Jakub - Horváth, A. - Malínský, Jan - Balážová, M.
Blocking phosphatidylglycerol degradation in yeast defective in cardiolipin remodeling results in a new model of the Barth syndrome cellular phenotype.
Journal of Biological Chemistry. Roč. 298, č. 1 (2022), č. článku 101462. ISSN 0021-9258. E-ISSN 1083-351X
R&D Projects: GA ČR(CZ) GA19-04052S
Institutional support: RVO:68378041
Keywords : saccharomyces-cerevisiae * mitochondrial phosphatidylethanolamine * lymphoblast mitochondria * phospholipase-C
OECD category: Cell biology
Impact factor: 4.8, year: 2022
Method of publishing: Open access
https://linkinghub.elsevier.com/retrieve/pii/S0021925821012710

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 pgc1Ataz1 Delta of Saccharomyces cerevisiae deficient in phosphatidylglycerol-specific phospholipase C and tafazzin as a new yeast model of BTHS. Unlike the taz1 Delta 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 taz1 Delta mutant. We also show that the mitochondria of the pgc1 Delta taz1 Delta 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 pgc1 Delta taz1 Delta mutant better mimics the cellular phenotype of BTHS patients than taz1 Delta 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.
Permanent Link: https://hdl.handle.net/11104/0338499