CELLULAR METABOLISM AND NON-CODING RNAs

Glucose, the main nutrient for mammalian cells, is used to obtain energy to sustain cellular processes through two integrated pathways: glycolysis and the tricarboxylic acid (TCA) cycle. Glycolysis and the TCA cycle are interconnected when pyruvate is converted into acetyl-Coa, which enters the TCA cycle in the mitochondria. In this second pathway, reducing equivalents (nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH)) are generated to serve as electron donors for the electron transport chain to fuel oxidative phosphorylation (OxPhos). Glycolysis generates 2 ATPs per molecule of glucose, whereas OxPhos generates up to 36 ATPs per glucose molecule. Under particular physiological conditions, cells also have the capability to metabolize other substrates (i.e glutamine of fatty acids) to replenish the TCA cycle and promote OxPhos. As multiple metabolic pathways intersect with each other at many levels in different cell types and conditions, eukaryotic cells face choices as to how to attain their metabolic goals.

Until recently cellular metabolism was considered a ‘house-keeping’ utility that merely supported cellular processes essential for survival through the production of ATP. However, it is now clear that the regulation of metabolic pathways provides a mechanism to actively control cellular growth and proliferation. The diametrically opposite cellular metabolic processes that are carried out in quiescent and proliferating cells clearly exemplify this paradigm. Quiescent cells mainly rely on mitochondrial OxPhos to generate energy, while proliferating cells metabolize nutrients primarily through aerobic glycolysis as a means to divert glycolytic intermediaries into biomass required to sustain proliferation. Moreover, it is now evident that metabolic choices also dictate cellular function and fate.

The relevance of the critical metabolic transitions between quiescence and proliferative states are mainly evident in a mammalian organism during immune responses and hematopoiesis. Although the signaling cascades that regulate cellular metabolism during immune responses are known, the function of non-coding RNAs as precise regulators of metabolic processes is largely unknown. We recently identified miR-181 as a central controller of cellular metabolism in vivo (Henao-Mejia et al., Immunity. 2013). Nonetheless, the full spectrum of biological functions of miR-181 in the context of immunity and metabolism remains to be elucidated. Moreover, the precise roles of most microRNAs and long noncoding intergenic RNAs (LincRNAs) in the regulation of cellular and whole body metabolism remain undetermined.

We are interested in using novel genetic tools to uncover the roles of novel non-coding RNAs in the immune system in vivo, with an emphasis in cellular metabolism.