Metabolic reprogramming during neuronal differentiation

TLDR

Neuronal differentiation involves sequential stages of migration, axon and dendrite development, and synaptic maturation. The study investigates how cellular metabolism and mitochondrial biology influence ex vivo differentiation of primary cortical neurons. The authors performed a global metabolic profiling of primary cortical neurons during ex vivo differentiation. Neuronal differentiation triggers massive mitochondrial biogenesis, heightened glucose uptake and metabolism, upregulation of GLUT3 and PFKp, increased glutamate–glutamine cycling, and is governed by PI3K‑Akt‑mTOR signaling, with pharmacological blockade revealing a metabolic checkpoint essential for 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.