Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.
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.
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
Xinde
X
Zheng
Laboratory of Genetics, Salk Institute, La Jolla, United States.
Leah
L
Boyer
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
Mingji
M
Jin
Laboratory of Genetics, Salk Institute, La Jolla, United States.
Jerome
J
Mertens
Laboratory of Genetics, Salk Institute, La Jolla, United States.
Yongsung
Y
Kim
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.|Gene Expression Laboratory, Salk Institute, La Jolla, United States.
Li
L
Ma
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.|Gene Expression Laboratory, Salk Institute, La Jolla, United States.
Li
L
Ma
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
Michael
M
Hamm
Laboratory of Genetics, Salk Institute, La Jolla, United States.
Fred H
FH
Gage
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
Tony
0000-0002-7691-6993
T
Hunter
D000332:Aerobiosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D006019:Glycolysis; D006801:Humans; D008660:Metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D010085:Oxidative Phosphorylation
LDHA; developmental biology; glycolysis; human; metabolism; neuronal differentiation; stem cell; stem cells; tricarboxylic acid cycle