PUBLICATION

Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation

Authors
Zielonka, M., Probst, J., Carl, M., Hoffmann, G.F., Kölker, S., Okun, J.G.
ID
ZDB-PUB-190118-9
Date
2019
Source
Experimental neurology   314: 91-99 (Journal)
Registered Authors
Carl, Matthias
Keywords
Bioenergetic impairment, Hyperammonemia, Neurotoxicity, Urea cycle disorders, Zebrafish
MeSH Terms
  • Adenosine Diphosphate/metabolism
  • Adenosine Triphosphate/deficiency
  • Adenosine Triphosphate/metabolism
  • Amino Acids, Branched-Chain/metabolism
  • Animals
  • Brain Chemistry
  • Citric Acid Cycle
  • Energy Metabolism*
  • Hyperammonemia/metabolism*
  • Ketoglutaric Acids/metabolism
  • Lactic Acid/metabolism
  • Larva
  • Neurotoxicity Syndromes/metabolism*
  • Oxidative Phosphorylation
  • Propionates/metabolism
  • Zebrafish
PubMed
30653968 Full text @ Exp. Neurol.
Abstract
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 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.
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