Nicotinamide riboside shows no benefit in mice with mitochondrial respiratory chain CIII deficiency

What is it about?

NAD+ is a central cofactor in numerous reduction-oxidation reactions in cells and its level is often decreased in diseases affecting energy metabolism. Vitamin B3s like niacin and nicotinamide riboside (NR) are utilized for NAD+ biosynthesis and, thus, feeding these vitamins can replenish the NAD+ pool. This, in turn, can improve mitochondrial function and ameliorate disease manifestation in animal models of mitochondrial diseases. The beneficial effect on mitochondrial function is thought to be mediated by sirtuin (SIRT) deacetylase enzymes that use NAD+ as a substrate. We found that Bcs1l mutant mice with respiratory chain complex III deficiency and mitochondrial hepatopathy have decreased NAD+ concentration in the liver due to decreased NAD+ biosynthesis. Aiming at ameliorating disease progression via NAD+ repletion and improved mitochondrial function, we fed NR to these mice. We found that hepatic NAD+ biosynthesis was enhanced upon NR, but NAD+ concentration at the end of treatment was unchanged. Contrary to our expectations, NR had no beneficial effect as the liver disease progression, survival and mitochondrial respiration were unchanged. We show that the mice had a starvation-like metabolic state in which SIRT1 and SIRT3 were already activated independently of NAD+, which likely explains the lack of therapeutic effect.

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Why is it important?

Mitochondrial disorders as a group are the most common inborn errors of metabolism (about 1 in 5000 births) but lack efficient treatments.

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