The M2 isoform of pyruvate kinase, the final rate-limiting enzyme of aerobic glycolysis, is expressed during embryonic development. In contrast, the M1 isoform is expressed in differentiated cells due to alternative splicing. Here we investigated murine embryonic stem cells (ESCs) with Pkm1 or Pkm2 knock-in alleles. Pkm1 allele knock-in resulted in excessive oxidative phosphorylation and induced the formation of cysteine-thiol disulfide-dependent complexes of forkhead box class-O (FOXO) transcription factors, which resulted in altered endoderm differentiation. In contrast, Pkm2 knock-in induced synthesis of a methylation-donor, S-adenosylmethionine, and increased unsaturated eicosanoid groups, which contributed to the redox control and maintenance of ESC undifferentiated status. Because PKM2 is also a critical enzyme for the cancer-specific Warburg effect, our results demonstrate an important role for the Pkm2 allele in establishing intracellular redox conditions and modulating PKM1-dependent oxidative phosphorylation events to achieve an appropriate ESC differentiation program.
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