Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models
Summary: Mitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer’s disease (AD), and the comprehension of the underlying mechanisms appears crucial to understand their relationship with the pathology....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720300851 |
| _version_ | 1818137306562822144 |
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| author | Alice Rossi Giulia Rigotto Giulia Valente Valentina Giorgio Emy Basso Riccardo Filadi Paola Pizzo |
| author_facet | Alice Rossi Giulia Rigotto Giulia Valente Valentina Giorgio Emy Basso Riccardo Filadi Paola Pizzo |
| author_sort | Alice Rossi |
| collection | DOAJ |
| description | Summary: Mitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer’s disease (AD), and the comprehension of the underlying mechanisms appears crucial to understand their relationship with the pathology. Using multiple genetic, pharmacological, imaging, and biochemical approaches, we demonstrate that, in different familial AD cell models, mitochondrial ATP synthesis is affected. The defect depends on reduced mitochondrial pyruvate oxidation, due to both lower Ca2+-mediated stimulation of the Krebs cycle and dampened mitochondrial pyruvate uptake. Importantly, this latter event is linked to glycogen-synthase-kinase-3β (GSK-3β) hyper-activation, leading, in turn, to impaired recruitment of hexokinase 1 (HK1) to mitochondria, destabilization of mitochondrial-pyruvate-carrier (MPC) complexes, and decreased MPC2 protein levels. Remarkably, pharmacological GSK-3β inhibition in AD cells rescues MPC2 expression and improves mitochondrial ATP synthesis and respiration. The defective mitochondrial bioenergetics influences glutamate-induced neuronal excitotoxicity, thus representing a possible target for future therapeutic interventions. : Mitochondria are key organelles for brain health. Rossi et al. show that, in different Alzheimer’s disease cell models, lower mitochondrial Ca2+ signal and pyruvate uptake reduce ATP synthesis. GSK-3β hyper-activation contributes to the defect by impairing HK1-mitochondria association, decreasing MPC2 levels and destabilizing MPC complexes. Defective bioenergetics affects neuronal functionality. Keywords: Alzheimer’s disease, presenilin, mitochondrial metabolism, bioenergetics, calcium homeostasis, pyruvate, mitochondrial pyruvate carrier, hexokinase 1, GSK-3b |
| first_indexed | 2024-12-11T09:54:12Z |
| format | Article |
| id | doaj.art-fdc78c49b4774370834040c16ee80882 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T09:54:12Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fdc78c49b4774370834040c16ee808822022-12-22T01:12:18ZengElsevierCell Reports2211-12472020-02-0130723322348.e10Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related ModelsAlice Rossi0Giulia Rigotto1Giulia Valente2Valentina Giorgio3Emy Basso4Riccardo Filadi5Paola Pizzo6Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, ItalyDepartment of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, ItalyDepartment of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, ItalyDepartment of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, ItalyDepartment of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, ItalyDepartment of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy; Corresponding authorDepartment of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy; Corresponding authorSummary: Mitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer’s disease (AD), and the comprehension of the underlying mechanisms appears crucial to understand their relationship with the pathology. Using multiple genetic, pharmacological, imaging, and biochemical approaches, we demonstrate that, in different familial AD cell models, mitochondrial ATP synthesis is affected. The defect depends on reduced mitochondrial pyruvate oxidation, due to both lower Ca2+-mediated stimulation of the Krebs cycle and dampened mitochondrial pyruvate uptake. Importantly, this latter event is linked to glycogen-synthase-kinase-3β (GSK-3β) hyper-activation, leading, in turn, to impaired recruitment of hexokinase 1 (HK1) to mitochondria, destabilization of mitochondrial-pyruvate-carrier (MPC) complexes, and decreased MPC2 protein levels. Remarkably, pharmacological GSK-3β inhibition in AD cells rescues MPC2 expression and improves mitochondrial ATP synthesis and respiration. The defective mitochondrial bioenergetics influences glutamate-induced neuronal excitotoxicity, thus representing a possible target for future therapeutic interventions. : Mitochondria are key organelles for brain health. Rossi et al. show that, in different Alzheimer’s disease cell models, lower mitochondrial Ca2+ signal and pyruvate uptake reduce ATP synthesis. GSK-3β hyper-activation contributes to the defect by impairing HK1-mitochondria association, decreasing MPC2 levels and destabilizing MPC complexes. Defective bioenergetics affects neuronal functionality. Keywords: Alzheimer’s disease, presenilin, mitochondrial metabolism, bioenergetics, calcium homeostasis, pyruvate, mitochondrial pyruvate carrier, hexokinase 1, GSK-3bhttp://www.sciencedirect.com/science/article/pii/S2211124720300851 |
| spellingShingle | Alice Rossi Giulia Rigotto Giulia Valente Valentina Giorgio Emy Basso Riccardo Filadi Paola Pizzo Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models Cell Reports |
| title | Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models |
| title_full | Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models |
| title_fullStr | Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models |
| title_full_unstemmed | Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models |
| title_short | Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models |
| title_sort | defective mitochondrial pyruvate flux affects cell bioenergetics in alzheimer s disease related models |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720300851 |
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