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

De novo NAD+ synthesis enhances mitochondrial function and improves health.

Author information

1
Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
2
Laboratory of Metabolic Signaling, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
3
Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
4
TES Pharma, Loc. Taverne, Corciano, Italy.
5
Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
6
Service of Endocrinology, Diabetes, Hypertension and Nutrition, Geneva University Hospitals, Geneva, Switzerland.
7
Molecular and Integrative Biology Lab, Healthy Aging-Korean Medical Research Center, Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, South Korea.
8
Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy.
9
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
10
Histology Core Facility, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
11
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
12
Intensive Care Unit, Department of Anaesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland.
13
Laboratory of Nephrology, Department of Internal Medicine Specialties and Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
14
Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.
15
TES Pharma, Loc. Taverne, Corciano, Italy. rpellicciari@tespharma.com.
16
Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. admin.auwerx@epfl.ch.

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.

PMID:
30356218
DOI:
10.1038/s41586-018-0645-6

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