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Munk SHN, Merchut-Maya JM, Adelantado Rubio A, Hall A, Pappas G, Milletti G, Lee M, Johnsen LG, Guldberg P, Bartek J, Maya-Mendoza A
Nat. Cell Biol. 25 (12) 1774-1786 [2023-12-00; online 2023-11-13]
The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD+) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD+ plays a key role in regulating metabolic pathways, such as glycolysis and Kreb's cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD+ to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD+ compromising cell viability. Therefore, the levels of NAD+ must be tightly regulated. Here we show that exogenous NAD+, but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD+ boosts Kreb's cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD+ results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD+ and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD+ regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy.
PubMed 37957325
DOI 10.1038/s41556-023-01280-z
Crossref 10.1038/s41556-023-01280-z
pmc: PMC10709141
pii: 10.1038/s41556-023-01280-z