4.6 Article

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

期刊

FEBS JOURNAL
卷 285, 期 18, 页码 3376-3401

出版社

WILEY
DOI: 10.1111/febs.14631

关键词

inborn errors of metabolism; metabolite repair; NAD(P)HX dehydratase; NAD(P)HX epimerase; Saccharomyces cerevisiae

资金

  1. Fonds National de la Recherche Luxembourg through an Inter-CORE grant [5773107]
  2. AFR PhD grant [4044610]
  3. CORE Junior grant [11339953]
  4. Fondation du Pelican de Mie et Pierre Hippert-Faber

向作者/读者索取更多资源

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.

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