Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models
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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.
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Glucose hypometabolism could be responsible for decreased ATP levels in the brain as observed, a drop in cognitive performances, and an upregulation of the main pathological markers in Alzheimer's disease.
“This glucose hypometabolism could be responsible for decreased ATP levels in the brain (Rossi et al., 2020) as we observed in our study, a drop in cognitive performances (El Hayek et al., 2019) and an upregulation of the main pathological markers in AD (Fu et al., 2015; Liu et al., 2004).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Rossi et al., 2020
The Abstract and In Brief report reduced mitochondrial ATP synthesis in Alzheimer’s disease cell models, supporting a link between impaired energy metabolism and ATP production. The Discussion says these models did not show reduced glycolysis and only speculates that reduced glucose uptake might worsen the defect in patients’ brains; it does not demonstrate that brain glucose hypometabolism caused decreased ATP levels. The cognitive-performance and pathological-marker claims are cited to other papers, not Rossi et al. (LLM, conf=0.86)
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The multifaceted pyruvate metabolism: role of the mitochondrial pyruvate carrier
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- Authors
- Rossi, A., Rigotto, G., Valente, G., Giorgio, V., Basso, E., Filadi, R., & Pizzo, P.
- Affiliations
- University of Padua (IT)
- Corresponding author
- Filadi, Riccardo
- Pizzo, Paola
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 30
- Issue
- 7
- Pages
- 2332-2348.e10
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3008327578
- Cited by
- 109
- References
- 9
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 11 · 2023: 17 · 2022: 15 · 2021: 28 · 2020: 11
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by-nc-nd)
- Funders
- Fondazione Cassa di Risparmio di Padova e Rovigo
- Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2017)
- Università degli Studi di Padova (SID 2019)
- F. Hoffmann-La Roche
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Alzheimer's disease, mitochondrial bioenergetics, GSK3β, hexokinase 1, mitochondrial pyruvate carrier, MPC2, TCA cycle, ATP production, mitochondrial respiration, glutamate excitotoxicity, excitotoxicity
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Energy Metabolism, Humans, Mitochondria, Transfection, Pyruvic Acid
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