Reference : NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/38086
NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells
English
Becker-Kettern, Julia mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Paczia, Nicole mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Conrotte, Jean-François mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Zhu, Chenchen []
Fiehn, Oliver []
Jung, Paul mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Steinmetz, Lars []
Linster, Carole mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
11-Aug-2018
FEBS Journal
Blackwell
Yes (verified by ORBilu)
International
1742-464X
1742-4658
Oxford
United Kingdom
[en] metabolite repair ; NAD(P)HX dehydratase ; NAD(P)HX epimerase ; Saccharomyces cerevisiae ; inborn errors of metabolism
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Enzymology & Metabolism (Linster Group)
Fonds National de la Recherche - FnR ; Fondation du Pélican de Mie et Pierre Hippert-Faber
Researchers
http://hdl.handle.net/10993/38086
10.1111/febs.14631.
https://febs.onlinelibrary.wiley.com/doi/abs/10.1111/febs.14631
FnR ; FNR4044610 > Julia Kettern > Metaboliterepair > Study of metabolite repair in eukaryotic cells > 01/04/2012 > 25/02/2017 > 2012

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