Universität zu Köln

Drews, Leonie, Zimmermann, Marcel, Westhoff, Philipp, Brilhaus, Dominik ORCID: 0000-0001-9021-3197, Poss, Rebecca E., Bergmann, Laura, Wiek, Constanze, Brenneisen, Peter, Piekorz, Roland P., Mettler-Altmann, Tabea, Weber, Andreas P. M. and Reichert, Andreas S. (2020). Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner. Dis. Model. Mech., 13 (10). CAMBRIDGE: COMPANY BIOLOGISTS LTD. ISSN 1754-8411

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Abstract

Astrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular, the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, in our analyses, within a timescale of minutes, mitochondrial respiration and glycolysis were hampered, which occurred in a pH-independent manner. Using metabolomics, an accumulation of glucose and numerous amino acids, including branched chain amino acids, was observed. Metabolomic tracking of N-15-labeled ammonia showed rapid incorporation of N-15 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. Metabolomic tracking of C-13-glutamine showed that hyperammonemia can inhibit anaplerosis of tricarboxylic acid (TCA) cycle intermediates. Contrary to its classical anaplerotic role, we show that, under hyperammonemia, GDH2 catalyzes the removal of ammonia by reductive amination of alpha-ketoglutarate, which efficiently and rapidly inhibits the TCA cycle. Overall, we propose a critical GDH2-dependent mechanism in HE models that helps to remove ammonia, but also impairs energy metabolism in mitochondria rapidly.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Drews, Leonie UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Marcel UNSPECIFIED UNSPECIFIED UNSPECIFIED Westhoff, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Brilhaus, Dominik UNSPECIFIED orcid.org/0000-0001-9021-3197 UNSPECIFIED Poss, Rebecca E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergmann, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiek, Constanze UNSPECIFIED UNSPECIFIED UNSPECIFIED Brenneisen, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Piekorz, Roland P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mettler-Altmann, Tabea UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Andreas P. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichert, Andreas S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-316083
DOI:	10.1242/dmm.047134
Journal or Publication Title:	Dis. Model. Mech.
Volume:	13
Number:	10
Date:	2020
Publisher:	COMPANY BIOLOGISTS LTD
Place of Publication:	CAMBRIDGE
ISSN:	1754-8411
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CULTURED RAT ASTROCYTES; HEPATIC-ENCEPHALOPATHY; MITOCHONDRIAL DYSFUNCTION; LIVER-DISEASE; AMINO-ACIDS; BRAIN; EXPRESSION; FAILURE; FISSION; SENESCENCE Multiple languages Cell Biology; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31608