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Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2014 Nov 07; Vol. 289 (45), pp. 31014-28. Date of Electronic Publication: 2014 Sep 18. - Publication Year :
- 2014
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Abstract
- 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.<br /> (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Adenosine Triphosphate chemistry
Animals
Carbon Dioxide chemistry
Cell Survival
Coculture Techniques
Fluoresceins chemistry
Glucose metabolism
Glycolysis
HEK293 Cells
Humans
Hydrogen Peroxide chemistry
Hydrogen-Ion Concentration
Lactates chemistry
Mice
Mitochondrial Uncoupling Proteins
Oxidative Phosphorylation
Oxygen Consumption
Astrocytes cytology
Gene Expression Regulation
Membrane Transport Proteins physiology
Mitochondria metabolism
Neurons cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 289
- Issue :
- 45
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25237189
- Full Text :
- https://doi.org/10.1074/jbc.M114.570879