SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells

Ozkan Ozden, Seong Hoon Park, Brett A. Wagner, Ha Yong Song, Yueming Zhu, Athanassios Vassilopoulos, Barbara Jung, Garry R. Buettner, David Gius*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

137 Scopus citations


Pyruvate dehydrogenase E1α (PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321), and a PDHA1 mutant mimicking a deacetylated lysine (PDHA1K321R) increases PDH activity, compared to the K321 acetylation mimic (PDHA1K321Q) or wild-type PDHA1. Finally, PDHA1K321Qexhibited a more transformed in vitro cellular phenotype compared to PDHA1K321R. These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyllysine, suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.

Original languageEnglish (US)
Pages (from-to)163-172
Number of pages10
JournalFree Radical Biology and Medicine
StatePublished - Nov 2014


  • Acetylation
  • Carcinogenesis
  • Free radicals
  • PDHA1
  • Pyruvate dehydrogenase
  • SIRT3
  • Warburg

ASJC Scopus subject areas

  • Physiology (medical)
  • Biochemistry


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