The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways.
A century after the identification of a coenzymatic activity for NAD(+), NAD(+) metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD(+) have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD(+)-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD(+) provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD(+)-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD(+) production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD(+); and 3) novel data that show how modulation of NAD(+)-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.
Houtkooper
Riekelt H
RH
Ecole Polytechnique Fédérale de Lausanne, Laboratory for Integrative and Systems Physiology, Building AI, Station 15, CH-1015 Lausanne, Switzerland.
Cantó
Carles
C
Wanders
Ronald J
RJ
Auwerx
Johan
J
D000818:Animals; D006801:Humans; D008659:Metabolic Diseases / Q000378:metabolism* / Q000628:therapy; D009243:NAD / Q000096:biosynthesis / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D009243:NAD; D010088:Oxidoreductases