期刊
DISEASE MODELS & MECHANISMS
卷 13, 期 10, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.047134
关键词
Hepatic encephalopathy; Hyperammonemia; Mitochondria; TCA cycle; Glutamate dehydrogenase; Brain energy metabolism
资金
- Deutsche Forschungsgemeinschaft (DFG) [CRC 974, CRC 1208]
- Stiftung fur Altersforschung der Heinrich-Heine-Universitat Dusseldorf [701 810 783]
- DFG under Germany's Excellence Strategy (EXC-2048/1) [390686111]
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.
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