Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival
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ArticleAuthors
Lambert, Hélène PerretenZenger, Manuel
Azarias, Guillaume
Chatton, Jean Yves
Magistretti, Pierre J.

Lengacher, Sylvain
KAUST Department
Bioscience ProgramBiological and Environmental Sciences and Engineering (BESE) Division
Date
2014-09-18Online Publication Date
2014-09-18Print Publication Date
2014-11-07Permanent link to this record
http://hdl.handle.net/10754/563762
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Brain activity is energetically costly and requires a steady and highly regulated flow of energy equivalents between neural cells. It is believed that a substantial share of cerebral glucose, the major source of energy of the brain, will preferentially be metabolized in astrocytes via aerobic glycolysis. The aim of this study was to evaluate whether uncoupling proteins (UCPs), located in the inner membrane of mitochondria, play a role in setting up the metabolic response pattern of astrocytes. UCPs are believed to mediate the transmembrane transfer of protons, resulting in the uncoupling of oxidative phosphorylation from ATP production. UCPs are therefore potentially important regulators of energy fluxes. The main UCP isoforms expressed in the brain are UCP2, UCP4, and UCP5. We examined in particular the role of UCP4 in neuron-astrocyte metabolic coupling and measured a range of functional metabolic parameters including mitochondrial electrical potential and pH, reactive oxygen species production, NAD/NADH ratio, ATP/ADP ratio, CO2 and lactate production, and oxygen consumption rate. In brief, we found that UCP4 regulates the intramitochondrial pH of astrocytes, which acidifies as a consequence of glutamate uptake, with the main consequence of reducing efficiency of mitochondrial ATP production. The diminished ATP production is effectively compensated by enhancement of glycolysis. This nonoxidative production of energy is not associated with deleterious H2O2 production. We show that astrocytes expressing more UCP4 produced more lactate, which is used as an energy source by neurons, and had the ability to enhance neuronal survival.Citation
Perreten Lambert, H., Zenger, M., Azarias, G., Chatton, J.-Y., Magistretti, P. J., & Lengacher, S. (2014). Control of Mitochondrial pH by Uncoupling Protein 4 in Astrocytes Promotes Neuronal Survival. Journal of Biological Chemistry, 289(45), 31014–31028. doi:10.1074/jbc.m114.570879Sponsors
This work was supported by Swiss National Science Foundation Grants 108336 (to P. J. M.) and 31003A-135720 (to J. Y. C.).Journal
Journal of Biological ChemistryPubMed ID
25237189PubMed Central ID
PMC4223307Additional Links
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223307http://www.jbc.org/content/289/45/31014.full.pdf
ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M114.570879
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