Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation

Abstract

SUMMARY Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during the zygotic genome activation (ZGA) at a 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 essential for epigenetic remodeling 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.

Long term effects of ART: What do animals tell us?

“…Amino acids for example act as signaling agents for trophectoderm differentiation and acquisition of invasive properties at the late blastocyst stage, their signaling activity relying on mTOR (mammalian Target of Rapamycin) activity and subsequent protein synthesis (Martin & Sutherland, ). Recently also, pyruvate has been shown to be necessary for the transient nuclear localization of some mitochondrial enzymes of the TCA cycle, which nuclear activity then induces post‐translational modifications of histones that are necessary for the transcriptional activation of the embryonic genome (EGA) (Nagaraj et al, ). Such a link between metabolic activity, epigenetic modifications and EGA may provide an explanation for the acute sensitivity of EGA stages to environmental changes.…”

The paradox of metabolism in quiescent stem cells

“…In human embryos as well, the enzyme pyruvate dehydrogenase is transiently localized to the nucleus at the time of human embryonic genome activation [157]. TCA enzymes can provide acetyl-CoA and a-ketoglutarate that can modify epigenetic marks in the nucleus, contribute to zygotic activation and allow continued embryo development [157]. The findings reinforce the close association between metabolic intermediates and epigenetic modifications, suggesting a partial TCA cycle may actually occur within the nucleus at the very beginning of an organism's life.…”

Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure

“…Central carbon metabolism affects various biological processes, such as cell proliferation and cell differentiation, while exerting housekeeping functions for cellular homeostasis (Pavlova & Thompson, 2016;Vander Heiden, Cantley, & Thompson, 2009). Coordinating metabolic rewiring with development in a spatiotemporal manner is essential for normal development (Agathocleous et al, 2012;Bulusu et al, 2017;Homem et al, 2014;Miyazawa et al, 2017;Nagaraj et al, 2017;Oginuma et al, 2017;Tennessen, Baker, Lam, Evans, & Thummel, 2011), in which developmental events are precisely coordinated in time and space. However, it remains to be shown how developing embryos couple energy metabolism with developmental progression.…”