Post-transcriptional regulation of energy usage: glucose and lipid metabolism

National Institute On Aging

Investigators

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Abstract

The studies in this Project focus on understanding the RNA-binding proteins (RBPs) and noncoding (nc)RNAs that influence energy metabolism, since the processes that generate energy become impaired with aging. In particular, we have studied the regulation of insulin production, adipogenesis, and myogenesis by RBPs and ncRNAs. GLUCOSE HOMEOSTASIS. With rising appreciation that glucose metabolism is extensively regulated at the post-transcriptional level, we continue efforts to identify regulators pancreatic cell function and glucose homeostasis. A mouse model is being generated that expresses HuD in pancreatic beta cells. MITOCHONDRIA. Over the past reporting period, we have made important progress towards understanding the role and metabolism of long noncoding (lnc)RNA in mitochondrial function. Some mitochondrial lncRNAs are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. One such nuclear DNA-encoded lncRNA, RMRP, was found to be the target of RBPs HuR and GRSF1, which associated with RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and exported it to the cytosol; subsequently, GRSF1 facilitated the function of RMRP in the mitochondria. Accordingly, silencing GRSF1 impaired the import of RMRP into mitochondria and lowered oxygen consumption rates. Our findings delineated a mechanism whereby RBPs mediate the transport of nuclear DNA-encoded lncRNAs into the mitochondria (Noh et al., Genes and Development, 2016). In this reporting period, we have investigated the roles of the mitochondrial RBP GRSF1 in the response to stresses causing cell sensecence (Noh et al., Nucleic Acids Res 2019). Ongoing studies are examining the impact of GRSF1 on the production and processing of mitochondrial RNAs including microRNAs, particularly as they impact mitochondrial activity. MYOGENESIS. During this review period, in collaboration with the Panda laboratory, we reported that microRNA miR-451a influenced production of SPARC during myogenesis regulatory factor (MRF) (Munk et al., PLoS ONE, 2019). In collaboration with Dr. Ferrucci (Translational Gerontology Branch) we examined macrophage polarization in aging skeletal muscle collected through the GESTALT project (Cui et al., Aging Cell, 2019). In ongoing studies, we are exploring the role of noncoding RNAs and circular RNAs in myogenesis using cell culture models. These studies are complemented by oingoing work within the GESTALT project to elucidate transcriptomic dynamics as a function of age.