高氨血症
柠檬酸循环
谷氨酰胺
谷氨酸脱氢酶
生物化学
尿素循环
糖酵解
氨基酸
三羧酸
生物
谷氨酸受体
谷氨酰胺合成酶
线粒体
新陈代谢
还原胺化
细胞呼吸
受体
精氨酸
催化作用
作者
Leonie Drews,Marcel Zimmermann,Philipp Westhoff,Dominik Brilhaus,Rebecca E. Poss,Laura Bergmann,Constanze Wiek,Peter Brenneisen,Roland P. Piekorz,Tabea Mettler‐Altmann,Andreas P.M. Weber,Andreas S. Reichert
摘要
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 15N-labeled ammonia showed rapid incorporation of 15N 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 13C-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 α-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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