SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells

Free Radic Biol Med. 2014 Nov;76:163-172. doi: 10.1016/j.freeradbiomed.2014.08.001. Epub 2014 Aug 22.

Abstract

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 (PDHA1(K321R)) increases PDH activity, compared to the K321 acetylation mimic (PDHA1(K321Q)) or wild-type PDHA1. Finally, PDHA1(K321Q) exhibited a more transformed in vitro cellular phenotype compared to PDHA1(K321R). 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.

Keywords: Acetylation; Carcinogenesis; Free radicals; PDHA1; Pyruvate dehydrogenase; SIRT3; Warburg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Blotting, Western
  • Cell Proliferation
  • Fluorescent Antibody Technique
  • Glucose / metabolism
  • Glycolysis
  • Humans
  • Immunoprecipitation
  • Lactic Acid / metabolism
  • Lysine / chemistry
  • Lysine / metabolism*
  • Neoplasms / enzymology*
  • Neoplasms / pathology
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Phenotype
  • Protein Processing, Post-Translational*
  • Pyruvate Dehydrogenase (Lipoamide) / metabolism*
  • Pyruvic Acid / metabolism*
  • Reactive Oxygen Species / metabolism
  • Sirtuin 3 / metabolism*
  • Tumor Cells, Cultured

Substances

  • Reactive Oxygen Species
  • Lactic Acid
  • Pyruvic Acid
  • Pyruvate Dehydrogenase (Lipoamide)
  • pyruvate dehydrogenase E1alpha subunit
  • SIRT3 protein, human
  • Sirtuin 3
  • Glucose
  • Lysine