De novo NAD + synthesis enhances mitochondrial function and improves health

Nature. 2018 Nov;563(7731):354-359. doi: 10.1038/s41586-018-0645-6. Epub 2018 Oct 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / metabolism
  • Carboxy-Lyases / antagonists & inhibitors
  • Carboxy-Lyases / chemistry
  • Carboxy-Lyases / deficiency
  • Carboxy-Lyases / metabolism*
  • Cell Line
  • Choline
  • Conserved Sequence*
  • Disease Models, Animal
  • Evolution, Molecular*
  • Female
  • Gene Knockdown Techniques
  • Health*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Homeostasis / drug effects
  • Humans
  • Kidney / cytology
  • Kidney / drug effects
  • Liver / cytology
  • Liver / drug effects
  • Longevity / drug effects
  • Male
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / physiology*
  • NAD / biosynthesis*
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Rats
  • Sirtuins / metabolism

Substances

  • NAD
  • Methionine
  • Sirtuins
  • Carboxy-Lyases
  • aminocarboxymuconate-semialdehyde decarboxylase
  • Choline