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.
Highlights
Neurons rely on oxidative phosphorylation to meet energy demands
We have uncovered several key molecular events underlying the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation
Downregulation of lactate dehydrogenase (LDHA) is a key switch for turning off aerobic glycolysis
Summary
Neurons rely on oxidative phosphorylation to meet energy demands. Malfunctions of mitochondrial oxidative phosphorylation (OXPHOS) lead to a wide range of neurological disorders, and are frequently observed in neurodegenerative diseases (Lin and Beal, 2006; Schon and Przedborski, 2011; Koopman et al, 2013). 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. Boyer et al have 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. The amounts of two proteins that regulate metabolism (called PGC-1a and ERRg) 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. OGDH, a key enzyme in the TCA cycle, has a novel and conserved neuronal splicing shift, resulting in the loss of a calcium binding motif
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