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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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).
Bolaños, J. P. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J. Neurochem. 139, 115–125 (2016).
Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).
Magistretti, P. J. Neuron-glia metabolic coupling and plasticity. J. Exp. Biol. 209, 2304–2311 (2006).
Perea, G., Sur, M. & Araque, A. Neuron-glia networks: integral gear of brain function. Front. Cell. Neurosci. 8, 378 (2014).
Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).
Pellerin, L. et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55, 1251–1262 (2007).
Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018).
Barros, L. F. Metabolic signaling by lactate in the brain. Trends Neurosci. 36, 396–404 (2013).
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).
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).
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).
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).
Ramos-Martinez, J. I. The regulation of the pentose phosphate pathway: remember Krebs. Arch. Biochem. Biophys. 614, 50–52 (2017).
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).
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).
Ago, T. et al. A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133, 978–993 (2008).
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).
Nayernia, Z., Jaquet, V. & Krause, K. H. New insights on NOX enzymes in the central nervous system. Antioxid. Redox Signal. 20, 2815–2837 (2014).
Pendyala, S. & Natarajan, V. Redox regulation of Nox proteins. Respir. Physiol. Neurobiol. 174, 265–271 (2010).
Kovac, S. et al. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim. Biophys. Acta 1850, 794–801 (2015).
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).
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).
Baxter, P. S. et al. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat. Commun. 6, 6761 (2015).
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).
Bobo-Jimenez, V. et al. APC/C(Cdh1)-Rock2 pathway controls dendritic integrity and memory. Proc. Natl Acad. Sci. USA 114, 4513–4518 (2017).
Young, D. et al. Protein promiscuity in H2O2 signaling. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2017.7013 (2018).
Weyand, C. M. & Goronzy, J. J. Immunometabolism in early and late stages of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 291–301 (2017).
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).
Kamat, C. D. et al. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J. Alzheimers Dis. 15, 473–493 (2008).
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).
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).
Latorre-Pellicer, A. et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535, 561–565 (2016).
Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).
Ristow, M. et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc. Natl Acad. Sci. USA 106, 8665–8670 (2009).
Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med 6, 221ra215 (2014).
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).
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).
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).
Quintana-Cabrera, R. & Bolaños, J. P. Glutathione and gamma-glutamylcysteine in hydrogen peroxide detoxification. Methods Enzymol. 527, 129–144 (2013).
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).
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).
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).
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).
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).
Lee, Y., Messing, A., Su, M. & Brenner, M. GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 56, 481–493 (2008).
Yardeni, T., Eckhaus, M., Morris, H. D., Huizing, M. & Hoogstraten-Miller, S. Retro-orbital injections in mice. Lab. Anim. (NY) 40, 155–160 (2011).
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).
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).
The authors declare no competing interests.
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Supplementary Figures 1–8 and Supplementary Table 5.
Differentially expressed transcripts in astrocytes from GFAP-mCAT and control mice.
Gene-annotation enrichment analysis and functional annotation clustering with DAVID and IMPaLA bioinformatics tools in astrocytes from GFAP-mCAT and control mice.
Normalized abundance values of filtered metabolites from the metabolomics study in the brain of GFAP-mCAT and control mice.
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.
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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