Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation

• Published in: Experimental neurology Vol. 314; pp. 91 - 99
• Main Authors: Zielonka, Matthias, Probst, Joris, Carl, Matthias, Hoffmann, Georg Friedrich, Kölker, Stefan, Okun, Jürgen Günther
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019
• Subjects: Adenosine Diphosphate - metabolism; Adenosine Triphosphate - deficiency; Adenosine Triphosphate - metabolism; Amino Acids, Branched-Chain - metabolism; Animals; Bioenergetic impairment; Brain Chemistry; Citric Acid Cycle; Energy Metabolism; Hyperammonemia; Hyperammonemia - metabolism; Ketoglutaric Acids - metabolism; Lactic Acid - metabolism; Larva; Neurotoxicity; Neurotoxicity Syndromes - metabolism; Oxidative Phosphorylation; Propionates - metabolism; Urea cycle disorders; Zebrafish; mM; CNS; ADP; M; NH4Ac; μM; Neurotoxicity; min; NMDA; ASL; dpf; hpf; Bioenergetic impairment; ARG1; Hyperammonemia; h; Zebrafish; Urea cycle disorders; ASS1; NaAc; s; TCA; CPS1; UCD; NAGS; ATP; HE; BCAA; OTC
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.01.008

Acute hyperammonemic encephalopathy is a life-threatening manifestation of individuals with urea cycle disorders, which is associated with high mortality rates and severe neurological sequelae in survivors. Cerebral bioenergetic failure has been proposed as one of the key mechanisms underlying hyperammonemia-induced brain damage, but data supporting this hypothesis remain inconclusive and partially contradictory. Using a previously established zebrafish model of acute hyperammonemic decompensation, we unraveled that acute hyperammonemia leads to a transamination-dependent withdrawal of 2-oxoglutarate (alpha-ketoglutarate) from the tricarboxylic acid (TCA) cycle with consecutive TCA cycle dysfunction, ultimately causing impaired oxidative phosphorylation with ATP shortage, decreased ATP/ADP-ratio and elevated lactate concentrations. Thus, our study supports and extends the hypothesis that cerebral bioenergetic dysfunction is an important pathophysiological hallmark of hyperammonemia-induced neurotoxicity. [Display omitted] •Acute hyperammonemia leads to withdrawal of alpha-ketoglutarate from the TCA cycle ultimately causing ATP shortage.•Increased propionate oxidation via activity of PCC-subunits PCCA and PCCB as major anaplerotic reaction becomes insufficient as hyperammonemia persists.•Glycolysis is enhanced in acute hyperammonemia as indicated by decreased glucose concentrations and elevated lactate levels.•Bioenergetic failure in acute hyperammonemia is time-dependent highlighting the need for urgent interventions.