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

Purhonen, Janne ; Rajendran, Jayasimman ; Tegelberg, Saara LU ; Smolander, Olli Pekka ; Pirinen, Eija ; Kallijärvi, Jukka LU and Fellman, Vineta LU orcid (2018) In FASEB Journal 32(11). p.5913-5926
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... (More)

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.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GRACILE syndrome, Mitochondrial disease, Nicotinamide riboside, Protein acetylation, Sirtuin
in
FASEB Journal
volume
32
issue
11
pages
14 pages
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • scopus:85055402685
  • pmid:29782205
ISSN
0892-6638
DOI
10.1096/fj.201800090R
language
English
LU publication?
yes
id
4542dcd8-f984-47b1-aa76-b9a8d3eafeac
date added to LUP
2018-11-14 14:21:31
date last changed
2021-10-06 02:49:18
@article{4542dcd8-f984-47b1-aa76-b9a8d3eafeac,
  abstract     = {<p>Biosynthetic precursors of NAD<sup>+</sup> can replenish a decreased cellular NAD<sup>+</sup> pool and, supposedly via sirtuin (SIRT) deacetylases, improvemitochondrial function.Wefound decreased hepaticNAD<sup>+</sup> concentration and downregulated biosynthesis in Bcs1l<sup>p.S78G</sup> knock-in mice with respiratory chain complex III deficiency and mitochondrial hepatopathy. Aiming at ameliorating disease progression via NAD<sup>+</sup> repletion and improved mitochondrial function, we fed thesemice nicotinamide riboside (NR), aNAD<sup>+</sup> precursor. A targetedmetabolomics verified successful administration and suggested enhancedNAD<sup>+</sup> biosynthesis in the treated mice, although hepaticNAD<sup>+</sup> concentrationwas unchanged at the end point. In contrast to our expectations,NRdid not improve the hepatopathy, hepatic mitochondrial respiration, or survival of Bcs1l<sup>p.S78G</sup> mice. We linked this lack of therapeutic effect to NAD<sup>+</sup>-independent activation of SIRT-1 and -3 via AMPK and cAMP signaling related to the starvation-like metabolic state of Bcs1l<sup>p.S78G</sup> mice. In summary, we describe an unusual metabolic state with NAD<sup>+</sup> 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.</p>},
  author       = {Purhonen, Janne and Rajendran, Jayasimman and Tegelberg, Saara and Smolander, Olli Pekka and Pirinen, Eija and Kallijärvi, Jukka and Fellman, Vineta},
  issn         = {0892-6638},
  language     = {eng},
  number       = {11},
  pages        = {5913--5926},
  publisher    = {The Federation of American Societies for Experimental Biology},
  series       = {FASEB Journal},
  title        = {NAD<sup>+</sup> repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation},
  url          = {http://dx.doi.org/10.1096/fj.201800090R},
  doi          = {10.1096/fj.201800090R},
  volume       = {32},
  year         = {2018},
}