Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer's Disease-Related Models
| Autor: | Alice Rossi, Paola Pizzo, Riccardo Filadi, Giulia Rigotto, Valentina Giorgio, Giulia Valente, Emy Basso |
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| Přispěvatelé: | Rossi A., Rigotto G., Valente G., Giorgio V., Basso E., Filadi R., Pizzo P. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pyruvate decarboxylation mitochondrial metabolism Bioenergetics Alzheimer's disease bioenergetics calcium homeostasis GSK-3b hexokinase 1 mitochondrial pyruvate carrier presenilin pyruvate calcium homeostasi Cell Excitotoxicity Mitochondrion medicine.disease_cause Transfection General Biochemistry Genetics and Molecular Biology Presenilin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Alzheimer Disease Pyruvic Acid medicine Animals Humans lcsh:QH301-705.5 Hexokinase ATP synthase biology bioenergetic Cell biology Mitochondria Disease Models Animal 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) chemistry biology.protein Energy Metabolism 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 30, Iss 7, Pp 2332-2348.e10 (2020) |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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