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NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

Julia Becker-Kettern, Nicole Paczia, Jean-François Conrotte, Chenchen Zhu, Oliver Fiehn, Paul P. Jung, Lars M. Steinmetz, Carole L. Linster
doi: https://doi.org/10.1101/302257
Julia Becker-Kettern
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg;
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Nicole Paczia
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg;
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Jean-François Conrotte
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg;
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Chenchen Zhu
2European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany;
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Oliver Fiehn
3NIH West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA;
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Paul P. Jung
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg;
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Lars M. Steinmetz
2European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany;
4Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA;
5Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Carole L. Linster
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg;
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  • For correspondence: carole.linster@uni.lu
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ABSTRACT

NADHX and NADPHX are hydrated and redox inactive forms of the NADH and NADPH cofactors, known to inhibit several dehydrogenases in vitro. A metabolite repair system that is conserved in all domains of life and that comprises the two enzymes NAD(P)HX dehydratase and NAD(P)HX epimerase, allows reconversion of both the S- and R-epimers of NADHX and NADPHX to the normal cofactors. An inherited deficiency in this system has recently been shown to cause severe neurometabolic disease in children. Although evidence for the presence of NAD(P)HX has been obtained in plant and human cells, little is known about the mechanism of formation of these derivatives in vivo and their potential effects on cell metabolism. Here, we show that NAD(P)HX dehydratase deficiency in yeast leads to an important, temperature-dependent NADHX accumulation in quiescent cells with a concomitant depletion of intracellular NAD+ and serine pools. We demonstrate that NADHX potently inhibits the first step of the serine synthesis pathway in yeast. Human cells deficient in the NAD(P)HX dehydratase also accumulated NADHX and showed decreased viability. In addition, those cells consumed more glucose and produced more lactate, potentially indicating impaired mitochondrial function. Our results provide first insights into how NADHX accumulation affects cellular functions and pave the way for a better understanding of the mechanism(s) underlying the rapid and severe neurodegeneration leading to early death in NADHX repair deficient children.

Abbreviations
αKG
α-ketoglutarate
2HG
2-hydroxyglutarate
GAPDH
glyceraldehyde-3-phosphate dehydrogenase
KO
knockout
NAXE
NAD(P)HX epimerase
NAXD
NAD(P)HX dehydratase
OD
optical density
3PGA
3-phosphoglycerate
PHGDH
phosphoglycerate dehydrogenase
3PHP
3-phosphohydroxypyruvate
3PSER
3-phosphoserine
ORF
open reading frame
PSAT1
phosphoserine transaminase 1

Footnotes

  • Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 05, 2018.
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NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells
Julia Becker-Kettern, Nicole Paczia, Jean-François Conrotte, Chenchen Zhu, Oliver Fiehn, Paul P. Jung, Lars M. Steinmetz, Carole L. Linster
bioRxiv 302257; doi: https://doi.org/10.1101/302257
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NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells
Julia Becker-Kettern, Nicole Paczia, Jean-François Conrotte, Chenchen Zhu, Oliver Fiehn, Paul P. Jung, Lars M. Steinmetz, Carole L. Linster
bioRxiv 302257; doi: https://doi.org/10.1101/302257

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