A Multi-Organ Role for Nocturnin in Post-Transcriptional Regulation of RNA

Nocturnin is an RNA-specific nuclease, a circadian deadenylase first discovered in the retina of Xenopus laevis, and is conserved among eukaryotes. Nocturnin is widely expressed in the brain and in the periphery and is also an immediate early gene that is acutely induced in response to various stimuli. This study investigates Nocturnin's potential role in post-transcriptional regulation of mRNAs in the mitochondria and in two different tissues: brain and brown adipose tissue (BAT). Nocturnin has a predicted mitochondrial-localization signal (MLS) surrounded by two potential translation initiation sites (AUG codons) raising the possibility of dual translation initiation sites. Here we demonstrate that Nocturnin is present in the mitochondria and that it exhibits mitochondrial or cytoplasmic localization via the use of alternative translation initiation sites. I also show that Nocturnin is acutely induced in response to cold and mitochondrial-encoded mRNAs in Noc-/- BAT exhibit impaired stability upon cold exposure. Global analysis of cold-induced changes in the transcriptome of Noc-/- and wild type (WT) mice reveal down-regulation of glycan biosynthesis genes in the Noc-/- BAT. Strikingly, metabolomics analysis demonstrates robust alterations in key tricarboxylic acid metabolites like pyruvate and succinate in the Noc-/- mice BAT in response to a prolonged cold exposure. In summary, we propose a model that Nocturnin acts as a metabolic switch in response to cold by diverting glucose and free fatty acids (FFA) to the mitochondria.
In this study, Nocturnin's potential role in post-transcriptional regulation of synaptic plasticity is also investigated. Activity-dependent local protein translation in the dendrites is thought to be an important component of synaptic plasticity. The mechanism of how translation of different mRNAs is differentially regulated in the dendrites is yet not clear. Here I demonstrate that Nocturnin is present in the dendrites as well as in the post-synaptic density as observed in cultured neurons and brain slices from cortex and hippocampus. I investigated mGluR-LTD in hippocampal slices from Noc-/- and WT littermates and observed an attenuation of mGluR-LTD in Noc-/- mice in the first cohort, but this result was not replicated in a second cohort. Further studies are needed to elucidate Nocturnin's role in the synapse.