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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Janne PurhonenVineta Fellman

Abstract

Biosynthetic precursors of NAD+ can replenish a decreased cellular NAD+ pool and, supposedly via sirtuin (SIRT) deacetylases, improve mitochondrial function. We found decreased hepatic NAD+ 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 these mice nicotinamide riboside (NR), a NAD+ precursor. A targeted metabolomics verified successful administration and suggested enhanced NAD+ biosynthesis in the treated mice, although hepatic NAD+ concentration was unchanged at the end point. In contrast to our expectations, NR did 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 und...Continue Reading

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Oct 12, 2018·Biochemical Society Transactions·Caterina Garone, Carlo Viscomi
Dec 12, 2018·EMBO Molecular Medicine·Jayasimman RajendranJukka Kallijärvi
Nov 2, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Nikica TomašićVineta Fellman
Feb 13, 2021·International Journal of Molecular Sciences·Andrey KropotovAndrey Nikiforov
Apr 10, 2021·Nature Communications·Roberta PeruzzoIldikò Szabò

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