NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation
(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.
(Less)
- author
- Purhonen, Janne ; Rajendran, Jayasimman ; Tegelberg, Saara LU ; Smolander, Olli Pekka ; Pirinen, Eija ; Kallijärvi, Jukka LU and Fellman, Vineta LU
- organization
- publishing date
- 2018
- 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
- Wiley
- external identifiers
-
- pmid:29782205
- scopus:85055402685
- 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
- 2024-02-14 12:27:39
@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}}, keywords = {{GRACILE syndrome; Mitochondrial disease; Nicotinamide riboside; Protein acetylation; Sirtuin}}, language = {{eng}}, number = {{11}}, pages = {{5913--5926}}, publisher = {{Wiley}}, 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}}, }