Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 76, Issue -, Pages 163-172Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2014.08.001
Keywords
Pyruvate dehydrogenase; SIRT3; PDHA1; Acetylation; Carcinogenesis; Warburg; Free radicals
Funding
- Hirshberg Foundation for Pancreatic Cancer Research Seed Grant Award
- [NCI-1R01CA152601-01]
- [1R01CA152799-01A1]
- [1R01CA168292-01A1]
- [1R01CA16383801A1]
- [NIH R01 CA169046]
- [NIH 5 P30 CA086862]
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Pyruvate dehydrogenase E1 alpha (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 wildtype 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. (C) 2014 Elsevier Inc. All rights reserved.
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