De novo NAD^sup +^ synthesis enhances mitochondrial function and improves health

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...

Full description

Saved in:
Bibliographic Details
Published inNature (London) Vol. 563; no. 7731; pp. 354 - 3
Main Authors Katsyuba, Elena, Mottis, Adrienne, Zietak, Marika, De Franco, Francesca, van der Velpen, Vera, Gariani, Karim, Ryu, Dongryeol, Cialabrini, Lucia, Matilainen, Olli, Liscio, Paride, Giacchè, Nicola, Stokar-Regenscheit, Nadine, Legouis, David, de Seigneux, Sophie, Ivanisevic, Julijana, Raffaelli, Nadia, Schoonjans, Kristina, Pellicciari, Roberto, Auwerx, Johan
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 15.11.2018
Subjects
Adenine
Biosynthesis
Homeostasis
Inhibitors
Kidneys
Life span
Liver
Liver diseases
Metabolism
Metabolites
Mitochondria
Mitochondrial DNA
NAD
Nematodes
Nicotinamide
Nicotinamide adenine dinucleotide
Oxidation
Pharmacology
Proteins
Substrates
Synthesis
Worms
Online AccessGet full text

Cover

More Information
Summary: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 a-aminoß-carboxymuconate-s-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of a-amino-ß-carboxymuconate-s-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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-018-0645-6