Cell 158, 84–97 (2014)

Histone acetylation, a post-translational modification and epigenetic regulator of gene expression in eukaryotes, is maintained by acetyltransferases that use acetyl-coenzyme A (Ac-CoA) as a substrate. The primary source of Ac-CoA in cells is the pyruvate dehydrogenase complex (PDC), a multiprotein enzyme that is typically localized in mitochondria. Because Ac-CoA contains a reactive thioester, it has remained unclear how the nucleus is able to obtain enough Ac-CoA to support histone modification. Sutendra et al. now show that PDC undergoes transport to the nucleus in a cell cycle–dependent manner where it generates Ac-CoA and facilitates histone acetylation. Using antibodies against all components of PDC, the authors visualized the complex in the nuclei of human sperm, normal fibroblasts and cancer cell lines. Immunoblotting identified assembled PDCs in highly purified nuclei preparations, and isotopic labeling and MS analysis revealed that the nuclear PDCs generate Ac-CoA in the presence of pyruvate. Nuclear synthesis of Ac-CoA is correlated with elevated histone acetylation, as validated by siRNA knockdown of a PDC component and selective inhibition of mitochondrial versus nuclear PDC. Cellular analysis showed that PDC from mitochondria is translocated to the nucleus at the S phase of the cell cycle in a process that is facilitated by the Hsp70 chaperone. The nuclear translocation of PDC is induced by signals including epidermal growth factor or mitochondrial stress, leading the authors to suggest that PDC-mediated nuclear production of Ac-CoA and histone acetylation is a key regulator of S phase cell-cycle entry.