Metabolic reprogramming during neuronal differentiation

Abstract

Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate–glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K–Akt–mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

“…6) argues that the splicing change of PKM is not merely a consequence of cell differentiation. A recent report indicated that mitochondrial bioenergetics and function are upregulated during neuronal differentiation (30). Moreover, fine-tuning of metabolic regulation is critical for the function and cell fate decisions of neural stem/progenitor cells (13-16), emphasizing the role of the PKM splicing switch in neurogenesis.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Mitochondrial biogenesis serves to increase mitochondrial mass, which is a necessary checkpoint for initiating neuronal differentiation and development (Agostini et al, 2016). Moreover, the stimulation of dendritic spine development by brainderived neurotrophic factor (BDNF) is, at least partly, dependent upon peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A, hereafter referred to as PGC1-α), a master transcriptional regulator of mitochondrial biogenesis (Cheng et al, 2012).…”

Effects of silica nanoparticle exposure on mitochondrial function during neuronal differentiation

“…MAP-K/ERK 1/2 was reported to be important for regulating mitochondrial function [11–13] as well as PI3-K/Akt/mechanistic target of rapamycin (mTOR) being a regulator in glucose metabolism during neuronal differentiation [14]. Phosphorylation of c-Jun N -terminal kinase (JNK), ERK and p38 mitogen-activated kinase (p38) were found in primary astrocytes after exposure to zinc oxide (ZnO) nanoparticles [15].…”