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Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons.

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posted on 22.11.2019 by Pierre Theurey, Niamh M. Connolly, Ilaria Fortunati, Emy Basso, Susette Lauwen, Camilla Ferrante, Catarina Moreira Pinho, Alvin Joselin, Anna Gioran, Daniele Bano, David S. Park, Maria Ankarcrona, Paola Pizzo, Jochen HM Prehn

Mitochondrial dysfunction is implicated in most neurodegenerative diseases, including Alzheimer's disease (AD). We here combined experimental and computational approaches to investigate mitochondrial health and bioenergetic function in neurons from a double transgenic animal model of AD (PS2APP/B6.152H). Experiments in primary cortical neurons demonstrated that AD neurons had reduced mitochondrial respiratory capacity. Interestingly, the computational model predicted that this mitochondrial bioenergetic phenotype could not be explained by any defect in the mitochondrial respiratory chain (RC), but could be closely resembled by a simulated impairment in the mitochondrial NADH flux. Further computational analysis predicted that such an impairment would reduce levels of mitochondrial NADH, both in the resting state and following pharmacological manipulation of the RC. To validate these predictions, we utilized fluorescence lifetime imaging microscopy (FLIM) and autofluorescence imaging and confirmed that transgenic AD neurons had reduced mitochondrial NAD(P)H levels at rest, and impaired power of mitochondrial NAD(P)H production. Of note, FLIM measurements also highlighted reduced cytosolic NAD(P)H in these cells, and extracellular acidification experiments showed an impaired glycolytic flux. The impaired glycolytic flux was identified to be responsible for the observed mitochondrial hypometabolism, since bypassing glycolysis with pyruvate restored mitochondrial health. This study highlights the benefits of a systems biology approach when investigating complex, nonintuitive molecular processes such as mitochondrial bioenergetics, and indicates that primary cortical neurons from a transgenic AD model have reduced glycolytic flux, leading to reduced cytosolic and mitochondrial NAD(P)H and reduced mitochondrial respiratory capacity.

Funding

Science Foundation Ireland, Grant/Award Number: 14/JPND/ B3077; Neuroscience Brain Canada/Krembil Foundation; Swedish Research Council, Grant/Award Number: 529-2014-7499; Canadian Institutes of Health Research; Bundesministerium für Bildung und Forschung, Grant/Award Number: BMBF; Ministero dell'Istruzione, dell'Università e della Ricerca, Grant/Award Number: DM 9; 08/01/2015; CeBioND EU Joint Programme for Neurodegenerative Disease Research (JPND; www.jpnd.eu)

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The original article is available at onlinelibrary.wiley.com

Published Citation

Theurey P, Connolly NMC, Fortunati I, Basso E, Lauwen S, Ferrante C, Moreira Pinho C, Joselin A, Gioran A, Bano D, Park DS, Ankarcrona M, Pizzo P, Prehn JHM. Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons. Aging Cell. 2019;18(3):e12924.

Publication Date

01/06/2019

Publisher

Wiley Online Library

PubMed ID

30793475

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