Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer's Disease-Related Models.

Autor:	Rossi A; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy., Rigotto G; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy., Valente G; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy., Giorgio V; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy., Basso E; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy., Filadi R; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy. Electronic address: riccardo.filadi@unipd.it., Pizzo P; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy; Neuroscience Institute - Italian National Research Council (CNR), Padua 35121, Italy. Electronic address: paola.pizzo@unipd.it.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Feb 18; Vol. 30 (7), pp. 2332-2348.e10.
DOI:	10.1016/j.celrep.2020.01.060
Abstrakt:	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 Ca 2+ -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. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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