期刊
CELL REPORTS
卷 30, 期 7, 页码 2332-2348出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.01.060
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资金
- Italian Ministry of University and Scientific Research
- University of Padua (SID)
- EU Joint Programme-Neurodegenerative Disease Research (CeBioND)
- Cassa di Risparmio di Padova e Rovigo Foundation (CARIPARO Starting Grant 2015)
- UNIPD Funds for Research Equipment (2015)
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-3 beta (GSK-3 beta) 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-3 beta 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.
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