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Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

Abstract

To satisfy its high energetic demand1, the brain depends on the metabolic cooperation of various cell types2,3,4. For example, astrocytic-derived lactate sustains memory consolidation5 by serving both as an oxidizable energetic substrate for neurons6 and as a signalling molecule7,8. Astrocytes and neurons also differ in the regulation of glycolytic enzymes9 and in the organization of their mitochondrial respiratory chain10. Unlike neurons, astrocytes rely on glycolysis for energy generation9 and, as a consequence, have a loosely assembled mitochondrial respiratory chain that is associated with a higher generation of mitochondrial reactive oxygen species (ROS)10. However, whether this abundant natural source of mitochondrial ROS in astrocytes fulfils a specific physiological role is unknown. Here we show that astrocytic mitochondrial ROS are physiological regulators of brain metabolism and neuronal function. We generated mice that inducibly overexpress mitochondrial-tagged catalase in astrocytes and show that this overexpression decreases mitochondrial ROS production in these cells during adulthood. Transcriptomic, metabolomic, biochemical, immunohistochemical and behavioural analysis of these mice revealed alterations in brain redox, carbohydrate, lipid and amino acid metabolic pathways associated with altered neuronal function and mouse behaviour. We found that astrocytic mitochondrial ROS regulate glucose utilization via the pentose-phosphate pathway and glutathione metabolism, which modulates the redox status and potentially the survival of neurons. Our data provide further molecular insight into the metabolic cooperation between astrocytes and neurons and demonstrate that mitochondrial ROS are important regulators of organismal physiology in vivo.

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Fig. 1: Generation of a conditional mouse with decreased mitochondrial ROS in astrocytes in cultured cells and in vivo.
Fig. 2: The pentose-phosphate pathway is increased and glycolysis is decreased in astrocytes from mCAT mice.
Fig. 3: Decreased Nrf2 transcriptional activity downmodulates NADPH(H+) oxidase–mediated extracellular superoxide in mCAT astrocytes and leads to neuronal damage.
Fig. 4: Decreased mitochondrial ROS in astrocytes in vivo shows signs compatible with alteration of neuronal structural integrity and causes cognitive impairment in mice.

Data availability

mRNA expression data have been deposited in Gene Expression Omnibus (GEO) under accession code GSE124130. Further information on statistical parameters, software, study design and so forth is in the Nature Research Reporting Summary. The data that support the findings of this study are available from the corresponding author upon reasonable request. All data generated or analysed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

We acknowledge the technical assistance of M. Resch, M. Carabias-Carrasco, L. Martin and E. Prieto-Garcia, from the University of Salamanca. This work was funded by MINECO (SAF2016-78114-R to J.P.B.), H2020 European Commission (BatCure grant 666918 to J.P.B.) and Fundación BBVA (to J.P.B.). A.A. is funded by H2020 European Commission (PANA grant 686009), Instituto de Salud Carlos III (PI15/00473 and RD16/0019/0018), Junta de Castilla y León (IES007P17) and Fundación Ramón Areces. J.A.E. is funded by MINECO (SAF2015-65633-R). The CNIC is supported by MINECO and Pro-CNIC Foundation, and is a SO-MINECO (award SEV-2015-0505). We thank the viral vector facility headed by A. Bemelmans for producing AAVs at MIRCen. This work was cofunded by FEDER. J.P.B. and J.A.E. are funded by CIBERFES (CB16/10/00282).

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Contributions

Conceived the idea: J.P.B. Performed experiments: C.V.-G., N.B., V.B.-J., D.J.-B., I.L.-F., E.F., C.J., G.B., A.A. Contributed materials: G.B., J.A.E. Wrote the manuscript: J.P.B. Edited and approved the manuscript: all co-authors.

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Correspondence to Juan P. Bolaños.

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Supplementary information

Supplementary Information

Supplementary Figures 1–8 and Supplementary Table 5.

Reporting Summary

Supplementary Table 1

Differentially expressed transcripts in astrocytes from GFAP-mCAT and control mice.

Supplementary Table 2

Gene-annotation enrichment analysis and functional annotation clustering with DAVID and IMPaLA bioinformatics tools in astrocytes from GFAP-mCAT and control mice.

Supplementary Table 3

Normalized abundance values of filtered metabolites from the metabolomics study in the brain of GFAP-mCAT and control mice.

Supplementary Table 4

Enrichment analysis according to the transcript expression in astrocytes and metabolite data in the brain by using the IMPaLA bioinformatics tool in FGAP-mCAT and control mice.

Supplementary Data 1

Source data for main and supplementary figures.

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Vicente-Gutierrez, C., Bonora, N., Bobo-Jimenez, V. et al. Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour. Nat Metab 1, 201–211 (2019). https://doi.org/10.1038/s42255-018-0031-6

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