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.

• MeSH
• acyltransferasy metabolismus   MeSH
• Barthův syndrom * metabolismus   MeSH
• fenotyp MeSH
• fosfatidylglyceroly * antagonisté a inhibitory   metabolismus   MeSH
• kardiolipiny * genetika   metabolismus   MeSH
• lidé MeSH
• Saccharomyces cerevisiae metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cationic colloidal gold nanorods (GNRs) have a great potential as a theranostic tool for diverse medical applications. GNRs' properties such as cellular internalization and stability are determined by physicochemical characteristics of their surface coating. GNRs modified by (16-mercaptohexadecyl)trimethylammonium bromide (MTAB), MTABGNRs, show excellent cellular uptake. Despite their promise for biomedicine, however, relatively little is known about the cellular pathways that facilitate the uptake of GNRs, their subcellular fate and intracellular persistence. Here we studied the mechanism of cellular internalization and long-term fate of GNRs coated with MTAB, for which the synthesis was optimized to give higher yield, in various human cell types including normal diploid versus cancerous, and dividing versus nondividing (senescent) cells. The process of MTABGNRs internalization into their final destination in lysosomes proceeds in two steps: (1) fast passive adhesion to cell membrane mediated by sulfated proteoglycans occurring within minutes and (2) slower active transmembrane and intracellular transport of individual nanorods via clathrin-mediated endocytosis and of aggregated nanorods via macropinocytosis. The expression of sulfated proteoglycans was the major factor determining the extent of uptake by the respective cell types. Upon uptake into proliferating cells, MTABGNRs were diluted equally and relatively rapidly into daughter cells; however, in nondividing/senescent cells the loss of MTABGNRs was gradual and very modest, attributable mainly to exocytosis. Exocytosed MTABGNRs can again be internalized. These findings broaden our knowledge about cellular uptake of gold nanorods, a crucial prerequisite for future successful engineering of nanoparticles for biomedical applications such as photothermal cancer therapy or elimination of senescent cells as part of the emerging rejuvenation approach.

• MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• endocytóza účinky léků   fyziologie   MeSH
• exocytóza * účinky léků   fyziologie   MeSH
• konfokální mikroskopie MeSH
• kultivační média MeSH
• kvartérní amoniové sloučeniny chemická syntéza   chemie   MeSH
• lidé MeSH
• lyzozomy účinky léků   MeSH
• mikroskopie elektronová rastrovací MeSH
• nádorové buněčné linie MeSH
• nanotrubičky analýza   chemie   MeSH
• polylysin chemie   farmakokinetika   MeSH
• proliferace buněk účinky léků   MeSH
• proteoglykany chemie   metabolismus   MeSH
• průtoková cytometrie MeSH
• stabilita léku MeSH
• sulfhydrylové sloučeniny chemie   MeSH
• techniky syntetické chemie MeSH
• zlato chemie   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH