Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42
Alzheimer’s disease (AD) is an incurable, age-related neurological disorder, the most common form of dementia. Considering that AD is a multifactorial complex disease, simplified experimental models are required for its analysis. For this purpose, genetically modified <i>Yarrowia lipolytica<...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/900 |
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| author | Khoren K. Epremyan Anton G. Rogov Tatyana N. Goleva Svetlana V. Lavrushkina Roman A. Zinovkin Renata A. Zvyagilskaya |
| author_facet | Khoren K. Epremyan Anton G. Rogov Tatyana N. Goleva Svetlana V. Lavrushkina Roman A. Zinovkin Renata A. Zvyagilskaya |
| author_sort | Khoren K. Epremyan |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is an incurable, age-related neurological disorder, the most common form of dementia. Considering that AD is a multifactorial complex disease, simplified experimental models are required for its analysis. For this purpose, genetically modified <i>Yarrowia lipolytica</i> yeast strains expressing Aβ42 (the main biomarker of AD), eGFP-Aβ42, Aβ40, and eGFP-Aβ40 were constructed and examined. In contrast to the cells expressing eGFP and eGFP-Aβ40, retaining “normal” mitochondrial reticulum, eGFP-Aβ42 cells possessed a disturbed mitochondrial reticulum with fragmented mitochondria; this was partially restored by preincubation with a mitochondria-targeted antioxidant SkQThy. Aβ42 expression also elevated ROS production and cell death; low concentrations of SkQThy mitigated these effects. Aβ42 expression caused mitochondrial dysfunction as inferred from a loose coupling of respiration and phosphorylation, the decreased level of ATP production, and the enhanced rate of hydrogen peroxide formation. Therefore, we have obtained the same results described for other AD models. Based on an analysis of these and earlier data, we suggest that the mitochondrial fragmentation might be a biomarker of the earliest preclinical stage of AD with an effective therapy based on mitochondria- targeted antioxidants. The simple yeast model constructed can be a useful platform for the rapid screening of such compounds. |
| first_indexed | 2024-03-09T12:28:37Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:28:37Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4e798124ed6943f89c80416b42d541152023-11-30T22:32:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-0124290010.3390/ijms24020900Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42Khoren K. Epremyan0Anton G. Rogov1Tatyana N. Goleva2Svetlana V. Lavrushkina3Roman A. Zinovkin4Renata A. Zvyagilskaya5A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, RussiaNational Research Center “Kurchatov Institute”, Akademika Kurchatova pl. 1, 123182 Moscow, RussiaA.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, RussiaBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory 1/40, 119992 Moscow, RussiaBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory 1/40, 119992 Moscow, RussiaA.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, RussiaAlzheimer’s disease (AD) is an incurable, age-related neurological disorder, the most common form of dementia. Considering that AD is a multifactorial complex disease, simplified experimental models are required for its analysis. For this purpose, genetically modified <i>Yarrowia lipolytica</i> yeast strains expressing Aβ42 (the main biomarker of AD), eGFP-Aβ42, Aβ40, and eGFP-Aβ40 were constructed and examined. In contrast to the cells expressing eGFP and eGFP-Aβ40, retaining “normal” mitochondrial reticulum, eGFP-Aβ42 cells possessed a disturbed mitochondrial reticulum with fragmented mitochondria; this was partially restored by preincubation with a mitochondria-targeted antioxidant SkQThy. Aβ42 expression also elevated ROS production and cell death; low concentrations of SkQThy mitigated these effects. Aβ42 expression caused mitochondrial dysfunction as inferred from a loose coupling of respiration and phosphorylation, the decreased level of ATP production, and the enhanced rate of hydrogen peroxide formation. Therefore, we have obtained the same results described for other AD models. Based on an analysis of these and earlier data, we suggest that the mitochondrial fragmentation might be a biomarker of the earliest preclinical stage of AD with an effective therapy based on mitochondria- targeted antioxidants. The simple yeast model constructed can be a useful platform for the rapid screening of such compounds.https://www.mdpi.com/1422-0067/24/2/900Alzheimer’s diseaseAβ42heterologous expressionyeast<i>Yarrowia lipolytica</i>cell death |
| spellingShingle | Khoren K. Epremyan Anton G. Rogov Tatyana N. Goleva Svetlana V. Lavrushkina Roman A. Zinovkin Renata A. Zvyagilskaya Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42 International Journal of Molecular Sciences Alzheimer’s disease Aβ42 heterologous expression yeast <i>Yarrowia lipolytica</i> cell death |
| title | Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42 |
| title_full | Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42 |
| title_fullStr | Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42 |
| title_full_unstemmed | Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42 |
| title_short | Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42 |
| title_sort | altered mitochondrial morphology and bioenergetics in a new yeast model expressing aβ42 |
| topic | Alzheimer’s disease Aβ42 heterologous expression yeast <i>Yarrowia lipolytica</i> cell death |
| url | https://www.mdpi.com/1422-0067/24/2/900 |
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