Moving towards a novel therapeutic strategy for hyperammonemia that targets glutamine metabolism. Issue 6 (4th August 2022)

• Record Type: Journal Article
• Authors: Fukui, Kaori; Takahashi, Tomoyuki; Matsunari, Hitomi; Uchikura, Ayuko; Watanabe, Masahito; Nagashima, Hiroshi; Ishihara, Naotada; Kakuma, Tatsuyuki; Watanabe, Yoriko; Yamashita, Yushiro; Yoshino, Makoto
• Is Part Of: Journal of inherited metabolic disease. Volume 45:Issue 6(2022)
• Page Start: 1059
• Page End: 1069
• Publication Date: 2022-08-04
• Subjects: anaplerosis -- glutamate dehydrogenase -- glutaminase -- glutaminolysis -- hyperammonemia -- ornithine transcarbamylase deficiency -- α‐ketoglutarate; Metabolism, Inborn errors of -- Periodicals; Metabolism -- Disorders -- Periodicals; 616.39042
• DOI: 10.1002/jimd.12540
• Languages: English
• ISSNs: 0141-8955

Abstract

Abstract: Patients with urea cycle disorders intermittently develop episodes of decompensation with hyperammonemia. Although such an episode is often associated with starvation and catabolism, its molecular basis is not fully understood. First, we attempted to elucidate the mechanism of such starvation‐associated hyperammonemia. Using a mouse embryonic fibroblast (MEF) culture system, we found that glucose starvation increases ammonia production, and that this increase is associated with enhanced glutaminolysis. These results led us to focus on α‐ketoglutarate (AKG), a glutamate dehydrogenase inhibitor, and a major anaplerotic metabolite. Hence, we sought to determine the effect of dimethyl α‐ketoglutarate (DKG), a cell‐permeable AKG analog, on MEFs and found that DKG mitigates ammonia production primarily by reducing flux through glutamate dehydrogenase. We also verified that DKG reduces ammonia in an NH4 Cl‐challenged hyperammonemia mouse model and observed that DKG administration reduces plasma ammonia concentration to 22.8% of the mean value for control mice that received only NH4 Cl. In addition, we detected increases in ornithine concentration and in the ratio of ornithine to arginine following DKG treatment. We subsequently administered DKG intravenously to a newborn pig with hyperammonemia due to ornithine transcarbamylase deficiency and found that blood ammonia concentration declined significantly over time. We determined that this effect is associated with facilitated reductive amination and glutamine synthesis. Our present data indicate that energy starvation triggers hyperammonemia through enhanced glutaminolysis and that DKG reduces ammonia accumulation via pleiotropic mechanisms both in vitro and in vivo. Thus, cell‐permeable forms of AKG are feasible candidates for a novel hyperammonemia treatment.