Free [NADH]/[NAD+] regulates sirtuin expression

Sirtuins are deacetylases involved in metabolic regulation and longevity. Our aim was to test the hypothesis that they are subjected to redox regulation by the [NADH]/[NAD+] ratio. We used NIH3T3 fibroblasts in culture, Drosophila fed with or without ethanol and exercising rats. In all three models an increase in [NADH]/[NAD+] came up with an increased expression of sirtuin mRNA and protein. PGC-1α (a substrate of sirtuins) protein level was significantly increased in fibroblasts incubated with lactate and pyruvate but this effect was lost in fibroblasts obtained from sirtuin-deficient mice.We conclude that the expression of sirtuins is subject to tight redox regulation by the [NADH]/[NAD+] ratio, which is a major sensor for metabolite availability conserved from invertebrates to vertebrates.

► The expression of sirtuins is regulated by the cytosolic [NADH]/[NAD+] redox ratio. ► The redox regulation of sirtuin expression is conserved from invertebrates to mammals. ► Ethanol feeding or exercise activates the expression of sirtuins. ► The expression of PGC1 is redox regulated mediated by sirtuins.