Identification of genes regulating cellular metabolism during human neurogenesis

Abstract

Metabolic reprogramming occurs during neuronal differentiation, but much about how noncoding elements affect the metabolic aspect of neurogenesis still needs exploration. Here, a novel facet of miR-124 in human neurogenesis as a driver of metabolic reprogramming is shown. A suppression of miR-124 by introducing miR-124 sponge to neural progenitor cells (NPCs) impairs neuronal development at the initiating stage of neurogenesis and alters cellular metabolism of differentiating neurons. To analyze the changes in neuronal differentiation by miR-124 on a systemic level, the neuronal proteome after depleting miR-124 was analyzed. By analyzing the proteome of differentiating neurons upon miR-124 knockdown via gene ontology (GO) analysis, differentially expressed proteins (DEPs) were linked to oxidative phosphorylation (OXPHOS) and metabolic pathways. In line with the proteome results, miR-124 depleted neurons displayed mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, miR-124 knockdown resulted in fragmented and immature mitochondria in early neurons. Collectively, this study suggests the roles of miR-124 in metabolic maturation at the early stages of neurogenesis. Further analysis of DEPs with predicted mitochondrial localization identified GSTK1 as one of the novel metabolic regulators of neurogenesis. A list of potential metabolic regulators at the initiating stages of neurogenesis as a result of miR-124 suppression propose the importance of miR-124 in the metabolic reprogramming of neurogenesis. Lastly, the necessity of discovering factors of metabolism related pathways or mitochondria in human neurogenesis is emphasized.