Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

Nature Metabolism volume 1, pages 201–211 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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).

References

  1. Bolaños, J. P. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J. Neurochem. 139, 115–125 (2016).

    Article  Google Scholar 

  2. Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).

    Article  CAS  Google Scholar 

  3. Magistretti, P. J. Neuron-glia metabolic coupling and plasticity. J. Exp. Biol. 209, 2304–2311 (2006).

    Article  CAS  Google Scholar 

  4. Perea, G., Sur, M. & Araque, A. Neuron-glia networks: integral gear of brain function. Front. Cell. Neurosci. 8, 378 (2014).

    Article  Google Scholar 

  5. Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).

    Article  CAS  Google Scholar 

  6. Pellerin, L. et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55, 1251–1262 (2007).

    Article  Google Scholar 

  7. Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018).

    Article  CAS  Google Scholar 

  8. Barros, L. F. Metabolic signaling by lactate in the brain. Trends Neurosci. 36, 396–404 (2013).

    Article  CAS  Google Scholar 

  9. Herrero-Mendez, A. et al. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat. Cell Biol. 11, 747–752 (2009).

    Article  CAS  Google Scholar 

  10. Lopez-Fabuel, I. et al. Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Proc. Natl Acad. Sci. USA 113, 13063–13068 (2016).

    Article  CAS  Google Scholar 

  11. Acin-Perez, R. et al. ROS-triggered phosphorylation of complex II by Fgr kinase regulates cellular adaptation to fuel use. Cell Metab. 19, 1020–1033 (2014).

    Article  CAS  Google Scholar 

  12. Hirrlinger, P. G., Scheller, A., Braun, C., Hirrlinger, J. & Kirchhoff, F. Temporal control of gene recombination in astrocytes by transgenic expression of the tamoxifen-inducible DNA recombinase variant CreERT2. Glia 54, 11–20 (2006).

    Article  Google Scholar 

  13. Ramos-Martinez, J. I. The regulation of the pentose phosphate pathway: remember Krebs. Arch. Biochem. Biophys. 614, 50–52 (2017).

    Article  CAS  Google Scholar 

  14. Coda, D. M. et al. SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma. Cell Cycle 14, 1389–1402 (2015).

    Article  CAS  Google Scholar 

  15. Winbanks, C. E. et al. TGF-beta regulates miR-206 and miR-29 to control myogenic differentiation through regulation of HDAC4. J. Biol. Chem. 286, 13805–13814 (2011).

    Article  CAS  Google Scholar 

  16. Ago, T. et al. A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133, 978–993 (2008).

    Article  CAS  Google Scholar 

  17. Bouzier-Sore, A. K. & Bolaños, J. P. Uncertainties in pentose-phosphate pathway flux assessment underestimate its contribution to neuronal glucose consumption: relevance for neurodegeneration and aging. Front. Aging Neurosci. 7, 89 (2015).

    Article  Google Scholar 

  18. Nayernia, Z., Jaquet, V. & Krause, K. H. New insights on NOX enzymes in the central nervous system. Antioxid. Redox Signal. 20, 2815–2837 (2014).

    Article  CAS  Google Scholar 

  19. Pendyala, S. & Natarajan, V. Redox regulation of Nox proteins. Respir. Physiol. Neurobiol. 174, 265–271 (2010).

    Article  CAS  Google Scholar 

  20. Kovac, S. et al. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim. Biophys. Acta 1850, 794–801 (2015).

    Article  CAS  Google Scholar 

  21. Suzuki, T. & Yamamoto, M. Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. J. Biol. Chem. 292, 16817–16824 (2017).

    Article  CAS  Google Scholar 

  22. Jimenez-Blasco, D., Santofimia-Castano, P., Gonzalez, A., Almeida, A. & Bolaños, J. P. Astrocyte NMDA receptors’ activity sustains neuronal survival through a Cdk5-Nrf2 pathway. Cell Death Differ. 22, 1877–1889 (2015).

    Article  CAS  Google Scholar 

  23. Baxter, P. S. et al. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat. Commun. 6, 6761 (2015).

    Article  CAS  Google Scholar 

  24. Diaz-Hernandez, J. I., Almeida, A., Delgado-Esteban, M., Fernandez, E. & Bolaños, J. P. Knockdown of glutamate-cysteine ligase by small hairpin RNA reveals that both catalytic and modulatory subunits are essential for the survival of primary neurons. J. Biol. Chem. 280, 38992–39001 (2005).

    Article  CAS  Google Scholar 

  25. Bobo-Jimenez, V. et al. APC/C(Cdh1)-Rock2 pathway controls dendritic integrity and memory. Proc. Natl Acad. Sci. USA 114, 4513–4518 (2017).

    Article  CAS  Google Scholar 

  26. Young, D. et al. Protein promiscuity in H2O2 signaling. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2017.7013 (2018).

  27. Weyand, C. M. & Goronzy, J. J. Immunometabolism in early and late stages of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 291–301 (2017).

    Article  CAS  Google Scholar 

  28. Cobley, J. N., Fiorello, M. L. & Bailey, D. M. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 15, 490–503 (2018).

    Article  CAS  Google Scholar 

  29. Kamat, C. D. et al. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J. Alzheimers Dis. 15, 473–493 (2008).

    Article  CAS  Google Scholar 

  30. Carvalho, A. N., Firuzi, O., Gama, M. J., Horssen, J. V. & Saso, L. Oxidative stress and antioxidants in neurological diseases: is there still hope? Curr. Drug Targets 18, 705–718 (2017).

    Article  CAS  Google Scholar 

  31. Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007).

    Article  CAS  Google Scholar 

  32. Latorre-Pellicer, A. et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535, 561–565 (2016).

    Article  CAS  Google Scholar 

  33. Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).

    Article  CAS  Google Scholar 

  34. Ristow, M. et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc. Natl Acad. Sci. USA 106, 8665–8670 (2009).

    Article  CAS  Google Scholar 

  35. Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med 6, 221ra215 (2014).

    Article  Google Scholar 

  36. Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297, 842–857 (2007).

    Article  CAS  Google Scholar 

  37. Nicholson, A. et al. Diet-induced obesity in two C57BL/6 substrains with intact or mutant nicotinamide nucleotide transhydrogenase (Nnt) gene. Obes. (Silver Spring). 18, 1902–1905 (2010).

    Article  CAS  Google Scholar 

  38. Acin-Perez, R., Fernandez-Silva, P., Peleato, M. L., Perez-Martos, A. & Enriquez, J. A. Respiratory active mitochondrial supercomplexes. Mol. Cell 32, 529–539 (2008).

    Article  CAS  Google Scholar 

  39. Quintana-Cabrera, R. & Bolaños, J. P. Glutathione and gamma-glutamylcysteine in hydrogen peroxide detoxification. Methods Enzymol. 527, 129–144 (2013).

    Article  CAS  Google Scholar 

  40. Li, Y., Zhu, H., Kuppusamy, P., Zweier, J. L. & Trush, M. A. Mitochondrial electron transport chain-derived superoxide exits macrophages: implications formononuclear cell-mediated pathophysiological processes. React. Oxyg. Species (Apex) 1, 81–98 (2016).

    Google Scholar 

  41. Tietze, F. Enzyme method for quantitative determination of nanogram amounts of total and oxidized glutathione: application to mammalian blood and other tissues. Anal. Biochem. 27, 502–522 (1969).

    Article  CAS  Google Scholar 

  42. Rodriguez-Rodriguez, P., Fernandez, E. & Bolaños, J. P. Underestimation of the pentose-phosphate pathway in intact primary neurons as revealed by metabolic flux analysis. J. Cereb. Blood Flow Metab. 33, 1843–1845 (2013).

    Article  CAS  Google Scholar 

  43. Larrabee, M. G. Evaluation of the pentose phosphate pathway from 14CO2 data: fallibility of a classic equation when applied to non-homogeneous tissues. Biochem. J. 272, 127–132 (1990).

    Article  CAS  Google Scholar 

  44. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    Article  CAS  Google Scholar 

  45. Lee, Y., Messing, A., Su, M. & Brenner, M. GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 56, 481–493 (2008).

    Article  Google Scholar 

  46. Yardeni, T., Eckhaus, M., Morris, H. D., Huizing, M. & Hoogstraten-Miller, S. Retro-orbital injections in mice. Lab. Anim. (NY) 40, 155–160 (2011).

    Article  Google Scholar 

  47. Almeida, A. & Medina, J. M. A rapid method for the isolation of metabolically active mitochondria from rat neurons and astrocytes in primary culture. Brain Res. Prot. 2, 209–214 (1998).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Author notes

  1. These authors contributed equally: Carlos Vicente-Gutierrez, Nicoló Bonora.

Authors and Affiliations

  1. Institute of Functional Biology and Genomics (IBFG), Universidad de Salamanca, CSIC, Salamanca, Spain

    Carlos Vicente-Gutierrez, Nicoló Bonora, Veronica Bobo-Jimenez, Daniel Jimenez-Blasco, Irene Lopez-Fabuel, Emilio Fernandez, Angeles Almeida & Juan P. Bolaños

  2. Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, Salamanca, Spain

    Carlos Vicente-Gutierrez, Nicoló Bonora, Veronica Bobo-Jimenez, Daniel Jimenez-Blasco, Irene Lopez-Fabuel, Emilio Fernandez, Angeles Almeida & Juan P. Bolaños

  3. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain

    Daniel Jimenez-Blasco, Emilio Fernandez, Jose A. Enriquez & Juan P. Bolaños

  4. Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d’Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, Fontenay-aux-Roses, France

    Charlene Josephine & Gilles Bonvento

  5. Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

    Jose A. Enriquez

Authors
  1. Carlos Vicente-Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicoló Bonora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Veronica Bobo-Jimenez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Jimenez-Blasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene Lopez-Fabuel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emilio Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charlene Josephine
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gilles Bonvento
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jose A. Enriquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Angeles Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Juan P. Bolaños
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Juan P. Bolaños.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-018-0031-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing