Ammonia inhibits energy metabolism in astrocytes in a rapid and GDH2-dependent manner

In hepatic encephalopathy (HE) astrocyte dysfunction is a primary factor impairing neuronal activity under hyperammonemia. We show that mitochondria in cellular HE models undergo rapid fragmentation under hyperammonemia in a reversible manner. Mitochondrial respiration and glycolysis were instantane...

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Published inbioRxiv
Main Authors Drews, Leonie, Zimmermann, Marcel, Poss, Rebecca E, Brilhaus, Dominik, Bergmann, Laura, Wiek, Constanze, Piekorz, Roland P, Weber, Andreas Pm, Mettler-Altmann, Tabea, Reichert, Andreas S
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.06.2019
Subjects
Amino acids
Ammonia
Animal models
Astrocytes
Dehydrogenases
Electron transport
Energy metabolism
Gene expression
Glutamate dehydrogenase
Glutamine
Glycolysis
Hepatic encephalopathy
Hyperammonemia
Ketoglutaric acid
Liver diseases
Mental disorders
Metabolism
Metabolomics
Mitochondria
Respiration
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Summary:In hepatic encephalopathy (HE) astrocyte dysfunction is a primary factor impairing neuronal activity under hyperammonemia. We show that mitochondria in cellular HE models undergo rapid fragmentation under hyperammonemia in a reversible manner. Mitochondrial respiration and glycolysis were instantaneously hampered in a pH-independent manner. A metabolomics approach revealed a subsequent accumulation of numerous amino acids, including branched chain amino acids, and glucose. N15-labeling of ammonia shows rapid incorporation of ammonia-derived nitrogen into glutamate and glutamate-derived amino acids. Downregulating human GLUD2, encoding mitochondrial glutamate dehydrogenase 2 (GDH2), inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Thus, under hyperammonemic conditions, GDH2 catalyzes the removal of ammonia by reductive amination of α-ketoglutarate, but at the same time inhibits the TCA-cycle by depleting α-ketoglutarate. Overall, we propose a mitochondria-dependent mechanism contributing to the early steps in the pathogenesis of HE where the interplay between energy metabolism and ammonia removal plays a pivotal role. Footnotes * Title and abstract shortened
DOI:10.1101/683763