Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation
Xinde Zheng,
Leah Boyer,
Mingji Jin,
Jerome Mertens,
Yongsung Kim,
Li Ma,
Li Ma,
Michael Hamm,
Fred H Gage,
Tony Hunter
Affiliations
Xinde Zheng
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
Leah Boyer
Laboratory of Genetics, Salk Institute, La Jolla, United States
Mingji Jin
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
Jerome Mertens
Laboratory of Genetics, Salk Institute, La Jolla, United States
Yongsung Kim
Laboratory of Genetics, Salk Institute, La Jolla, United States
Li 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 Ma
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States; Gene Expression Laboratory, Salk Institute, La Jolla, United States
Michael Hamm
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
Fred H Gage
Laboratory of Genetics, Salk Institute, La Jolla, United States
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.
