Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation

Abstract

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.

DOI: http://dx.doi.org/10.7554/eLife.13374.001

eLife digest

Structures called mitochondria act like the batteries of cells, and use several different metabolic processes to release energy. For example, neurons rely on a metabolic process called oxidative phosphorylation, while neural progenitor cells (which develop, or differentiate, into neurons) use a process called aerobic glycolysis instead. Little is known about why neurons prefer to use oxidative phosphorylation to provide them with energy, and it is also not clear why problems that affect this process are often seen in neurological disorders and neurodegenerative diseases.

Zheng, Boyer et al. have now used human neural progenitor cells to explore the metabolic changes that occur as these cells develop into neurons. It appears that the loss of two metabolic enzymes, called hexokinase and lactate dehydrogenase, marks the transition from aerobic glycolysis to oxidative phosphorylation. In addition, the instructions to produce an enzyme called pyruvate kinase are altered or “alternatively spliced” when progenitor cells differentiate, which in turn changes the structure of the enzyme. The levels of the proteins that activate and regulate the production of these three metabolic enzymes also decrease dramatically during this transition. Further experiments showed that neurons that produce hexokinase and lactate dehydrogenase while they differentiate die, which means that neurons must shut off aerobic glycolysis in order to survive.

The amounts of two proteins that regulate metabolism (called PGC-1α and ERRγ) increase significantly when a neuron differentiates. This sustains a constant level of activity for several metabolic and mitochondrial genes as neural progenitor cells differentiate to form neurons. Zheng, Boyer et al. also found that neurons build more mitochondria as they grow; this suggests that an unknown mechanism exists that links the creation of mitochondria to the size of the neuron.

Zheng, Boyer et al. have mainly focused on how much of each metabolic enzyme is produced inside cells, but these levels may not completely reflect the actual level of enzyme activity. The next steps are therefore to investigate whether any other processes or modifications play a part in regulating the enzymes. Further investigation is also needed to determine the effects of changes in mitochondrial structure that occur as a neuron develops from a neural progenitor cell.

DOI: http://dx.doi.org/10.7554/eLife.13374.002