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Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation

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 hyper...

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Bibliographic Details
Main Authors: Zielonka, Matthias (Author) , Probst, Joris (Author) , Carl, Matthias (Author) , Hoffmann, Georg F. (Author) , Kölker, Stefan (Author) , Okun, Jürgen G. (Author)
Format: Article (Journal)
Language:English
Published: 14 January 2019
In: Experimental neurology
Year: 2019, Volume: 314, Pages: 91-99
ISSN:1090-2430
DOI:10.1016/j.expneurol.2019.01.008
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.expneurol.2019.01.008
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0014488618305004
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Author Notes:Matthias Zielonka, Joris Probst, Matthias Carl, Georg Friedrich Hoffmann, Stefan Kölker, Jürgen Günther Okun
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Summary: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.
Item Description:Gesehen am 27.03.2019
Physical Description:Online Resource
ISSN:1090-2430
DOI:10.1016/j.expneurol.2019.01.008

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