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The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes.
- Source :
-
Journal of neuroscience research [J Neurosci Res] 2017 Nov; Vol. 95 (11), pp. 2307-2320. Date of Electronic Publication: 2017 Mar 19. - Publication Year :
- 2017
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Abstract
- Metformin is an antidiabetic drug that is used daily by millions of patients worldwide. Metformin is able to cross the blood-brain barrier and has recently been shown to increase glucose consumption and lactate release in cultured astrocytes. However, potential effects of metformin on mitochondrial tricarboxylic acid (TCA) cycle metabolism in astrocytes are unknown. We investigated this by mapping <superscript>13</superscript> C labeling in TCA cycle intermediates and corresponding amino acids after incubation of primary rat astrocytes with [U- <superscript>13</superscript> C]glucose. The presence of metformin did not compromise the viability of cultured astrocytes during 4 hr of incubation, but almost doubled cellular glucose consumption and lactate release. Compared with control cells, the presence of metformin dramatically lowered the molecular <superscript>13</superscript> C carbon labeling (MCL) of the cellular TCA cycle intermediates citrate, α-ketoglutarate, succinate, fumarate, and malate, as well as the MCL of the TCA cycle intermediate-derived amino acids glutamate, glutamine, and aspartate. In addition to the total molecular <superscript>13</superscript> C labeling, analysis of the individual isotopomers of TCA cycle intermediates confirmed a severe decline in labeling and a significant lowering in TCA cycling ratio in metformin-treated astrocytes. Finally, the oxygen consumption of mitochondria isolated from metformin-treated astrocytes was drastically reduced in the presence of complex I substrates, but not of complex II substrates. These data demonstrate that exposure to metformin strongly impairs complex I-mediated mitochondrial respiration in astrocytes, which is likely to cause the observed decrease in labeling of mitochondrial TCA cycle intermediates and the stimulation of glycolytic lactate production. © 2017 Wiley Periodicals, Inc.<br /> (© 2017 Wiley Periodicals, Inc.)
- Subjects :
- Animals
Animals, Newborn
Astrocytes metabolism
Cell Respiration drug effects
Cell Respiration physiology
Cells, Cultured
Citric Acid Cycle physiology
Mitochondria metabolism
Oxygen Consumption drug effects
Oxygen Consumption physiology
Rats
Rats, Wistar
Astrocytes drug effects
Citric Acid Cycle drug effects
Hypoglycemic Agents pharmacology
Metformin pharmacology
Mitochondria drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4547
- Volume :
- 95
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of neuroscience research
- Publication Type :
- Academic Journal
- Accession number :
- 28316081
- Full Text :
- https://doi.org/10.1002/jnr.24050