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.
Citation
Zielonka, M., Probst, J., Carl, M., Hoffmann, G.F., Kölker, S., Okun, J.G. (2019) Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation. Experimental neurology. 314:91-99.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping