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De novo NAD+ synthesis enhances mitochondrial function and improves health

Author

Listed:
  • 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
    Polish Academy of Sciences)

  • Francesca Franco

    (Loc. Taverne)

  • Vera Velpen

    (University of Lausanne)

  • Karim Gariani

    (Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
    Geneva University Hospitals)

  • Dongryeol Ryu

    (Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
    School of Korean Medicine, Pusan National University)

  • Lucia Cialabrini

    (Polytechnic University of Marche)

  • Olli Matilainen

    (Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne
    University of Helsinki)

  • Paride Liscio

    (Loc. Taverne)

  • Nicola Giacchè

    (Loc. Taverne)

  • Nadine Stokar-Regenscheit

    (École Polytechnique Fédérale de Lausanne
    Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche)

  • David Legouis

    (University Hospital of Geneva
    University of Geneva)

  • Sophie Seigneux

    (University of Geneva
    University Hospital 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)

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.

Suggested Citation

  • Elena Katsyuba & Adrienne Mottis & Marika Zietak & Francesca Franco & Vera Velpen & Karim Gariani & Dongryeol Ryu & Lucia Cialabrini & Olli Matilainen & Paride Liscio & Nicola Giacchè & Nadine Stokar-, 2018. "De novo NAD+ synthesis enhances mitochondrial function and improves health," Nature, Nature, vol. 563(7731), pages 354-359, November.
  • Handle: RePEc:nat:nature:v:563:y:2018:i:7731:d:10.1038_s41586-018-0645-6
    DOI: 10.1038/s41586-018-0645-6
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    Citations

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    Cited by:

    1. Di-Yang Sun & Wen-Bin Wu & Jian-Jin Wu & Yu Shi & Jia-Jun Xu & Shen-Xi Ouyang & Chen Chi & Yi Shi & Qing-Xin Ji & Jin-Hao Miao & Jiang-Tao Fu & Jie Tong & Ping-Ping Zhang & Jia-Bao Zhang & Zhi-Yong Li, 2024. "Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Hope Dang & Raul Castro-Portuguez & Luis Espejo & Grant Backer & Samuel Freitas & Erica Spence & Jeremy Meyers & Karissa Shuck & Emily A. Gardea & Leah M. Chang & Jonah Balsa & Niall Thorns & Caroline, 2023. "On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Nan Wu & Yi-Cheng Ma & Xin-Qian Gong & Pei-Ji Zhao & Yong-Jian Jia & Qiu Zhao & Jia-Hong Duan & Cheng-Gang Zou, 2023. "The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Markus M. Rinschen & Oleg Palygin & Ashraf El-Meanawy & Xavier Domingo-Almenara & Amelia Palermo & Lashodya V. Dissanayake & Daria Golosova & Michael A. Schafroth & Carlos Guijas & Fatih Demir & Johan, 2022. "Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Quetzalcoatl Escalante-Covarrubias & Lucía Mendoza-Viveros & Mirna González-Suárez & Román Sitten-Olea & Laura A. Velázquez-Villegas & Fernando Becerril-Pérez & Ignacio Pacheco-Bernal & Erick Carreño-, 2023. "Time-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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