De novo NAD+ synthesis enhances mitochondrial function and improves health

Elena Katsyuba, Adrienne Mottis, Marika Zietak, Francesca Franco, Vera Velpen, Karim Gariani, Dongryeol Ryu, Lucia Cialabrini, Olli Matilainen, Paride Liscio, Nicola Giacchè, Nadine Stokar-Regenscheit, David Legouis, Sophie Seigneux, Julijana Ivanisevic, Nadia Raffaelli, Kristina Schoonjans, Roberto Pellicciari () and Johan Auwerx ()
Additional contact information
Elena Katsyuba: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Adrienne Mottis: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Marika Zietak: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Francesca Franco: Loc. Taverne
Vera Velpen: University of Lausanne
Karim Gariani: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Dongryeol Ryu: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Lucia Cialabrini: Polytechnic University of Marche
Olli Matilainen: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Paride Liscio: Loc. Taverne
Nicola Giacchè: Loc. Taverne
Nadine Stokar-Regenscheit: École Polytechnique Fédérale de Lausanne
David Legouis: University Hospital of Geneva
Sophie Seigneux: University of Geneva
Julijana Ivanisevic: University of Lausanne
Nadia Raffaelli: Polytechnic University of Marche
Kristina Schoonjans: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
Roberto Pellicciari: Loc. Taverne
Johan Auwerx: Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne

Nature, 2018, vol. 563, issue 7731, 354-359

Abstract: Abstract Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. We also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, we identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.

Keywords: Sirtuins (SIRT1); SIRT1 Activation; Quinolinate Phosphoribosyltransferase (QPRT); Non-alcoholic Fatty Liver Disease (NAFLD); Mediate RNA Interference (RNAi) (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (5)

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DOI: 10.1038/s41586-018-0645-6

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