Cell
Volume 168, Issues 1–2, 12 January 2017, Pages 210-223.e11
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Article
Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation

https://doi.org/10.1016/j.cell.2016.12.026Get rights and content
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Highlights

  • A subclass of active mitochondrial TCA cycle enzymes transiently moves to the nucleus

  • Nuclear TCA proteins and metabolites are essential for zygotic genome activation (ZGA)

  • Pyruvate, O-glycosylation, and chaperones are essential for this nuclear localization

  • In both human and mouse embryos, PDH is nuclear when ZGA occurs in these species

Summary

Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during zygotic genome activation (ZGA) at the 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle are essential for epigenetic remodeling and are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development.

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