NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation

Research output: Contribution to journalArticle

Abstract

Biosynthetic precursors of NAD+ can replenish a decreased cellular NAD+ pool and, supposedly via sirtuin (SIRT) deacetylases, improvemitochondrial function.Wefound decreased hepaticNAD+ concentration and downregulated biosynthesis in Bcs1lp.S78G knock-in mice with respiratory chain complex III deficiency and mitochondrial hepatopathy. Aiming at ameliorating disease progression via NAD+ repletion and improved mitochondrial function, we fed thesemice nicotinamide riboside (NR), aNAD+ precursor. A targetedmetabolomics verified successful administration and suggested enhancedNAD+ biosynthesis in the treated mice, although hepaticNAD+ concentrationwas unchanged at the end point. In contrast to our expectations,NRdid not improve the hepatopathy, hepatic mitochondrial respiration, or survival of Bcs1lp.S78G mice. We linked this lack of therapeutic effect to NAD+-independent activation of SIRT-1 and -3 via AMPK and cAMP signaling related to the starvation-like metabolic state of Bcs1lp.S78G mice. In summary, we describe an unusual metabolic state with NAD+ depletion accompanied by energy deprivation signals, uncompromised SIRT function, and upregulated oxidative metabolism. Our study highlights that the knowledge of the underlying complexmetabolic alterations is criticalwhen designing therapies formitochondrial dysfunction.

Details

Authors
  • Janne Purhonen
  • Jayasimman Rajendran
  • Saara Tegelberg
  • Olli Pekka Smolander
  • Eija Pirinen
  • Jukka Kallijärvi
  • Vineta Fellman
Organisations
External organisations
  • University of Helsinki
  • Folkhälsan Research Center
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • GRACILE syndrome, Mitochondrial disease, Nicotinamide riboside, Protein acetylation, Sirtuin
Original languageEnglish
Pages (from-to)5913-5926
Number of pages14
JournalFASEB Journal
Volume32
Issue number11
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes