Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway

Martin R. Späth, K. Johanna R. Hoyer-Allo, Lisa Seufert, Martin Höhne, Christina Lucas, Theresa Bock, Lea Isermann, Susanne Brodesser, Jan Wilm Lackmann, Katharina Kiefer, Felix C. Koehler, Katrin Bohl, Michael Ignarski, Petra Schiller, Marc Johnsen, Torsten Kubacki, Franziska Grundmann, Thomas Benzing, Aleksandra Trifunovic, Marcus KrügerBernhard Schermer, Volker Burst, Roman Ulrich Müller

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Significance StatementAKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort.BackgroundClinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown.MethodsKynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation.ResultsWe identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans.ConclusionsCR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

Original languageEnglish
Pages (from-to)772-792
Number of pages21
JournalJournal of the American Society of Nephrology
Issue number5
StatePublished - 1 May 2023
Externally publishedYes


  • AKI
  • AKI
  • NAD+ pathway
  • acetylation
  • caloric restriction
  • kynu
  • nicotinamide
  • organ protection
  • preconditioning
  • tryptophan


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