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

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 Bcs1l(p.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 Bcs1l(p.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 Bcs1l(p.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 complex metabolic alterations is critical when designing therapies for mitochondrial dysfunction.Purhonen, J., Rajendran, J., Tegelberg, S., Smolander, O.-P., Pirinen, E., Kallijarvi, J., Fellman, V. NAD(+) repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation.