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

In English

Författare

  • Janne Purhonen
  • Jayasimman Rajendran
  • Saara Tegelberg
  • Olli Pekka Smolander
  • Eija Pirinen
  • Jukka Kallijärvi
  • Vineta Fellman

Summary, in English

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.

Avdelning/ar

Publiceringsår

2018

Språk

Engelska

Sidor

5913-5926

Publikation/Tidskrift/Serie

FASEB Journal

Volym

32

Avvikelse

11

Dokumenttyp

Artikel i tidskrift

Förlag

Wiley

Ämne

  • Cell and Molecular Biology

Nyckelord

  • GRACILE syndrome
  • Mitochondrial disease
  • Nicotinamide riboside
  • Protein acetylation
  • Sirtuin

Aktiv

Published

ISBN/ISSN/Övrigt

  • ISSN: 0892-6638