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

doi:10.1016/j.freeradbiomed.2014.08.001

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SIRT3 DEACETYLATES AND INCREASES PYRUVATE DEHYDROGENASE ACTIVITY IN CANCER CELLS

Journal article

Peer reviewed

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 and David Gius

Free radical biology & medicine, Vol.76, pp.163-172

11/2014

DOI: 10.1016/j.freeradbiomed.2014.08.001

PMCID: PMC4364304

PMID: 25152236

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Abstract

Pyruvate dehydrogenase E1 alpha (PDHE1α or PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex (PDC) 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 in PDH activity, as compared to the K321 acetylation mimic ( PDHA1 K321Q ) or wild-type PDHA1 . Finally, PDHA1 K321Q exhibited a more transformed in vitro cellular phenotype as 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 acetyl-lysine suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.

Pyruvate dehydrogenase

Warburg

PDHA1

Acetylation

Carcinogenesis

SIRT3

Details

Title: Subtitle: SIRT3 DEACETYLATES AND INCREASES PYRUVATE DEHYDROGENASE ACTIVITY IN CANCER CELLS
Creators: Ozkan Ozden - Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Seong-Hoon Park - Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Brett A Wagner - Department of Radiation Oncology, Free Radical and Radiation Biology, The University of Iowa, Iowa City, IA 52242
Ha Yong Song - Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Yueming Zhu - Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Athanassios Vassilopoulos - Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Barbara Jung - Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612
Garry R Buettner - Department of Radiation Oncology, Free Radical and Radiation Biology, The University of Iowa, Iowa City, IA 52242
David Gius - Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.76, pp.163-172
DOI: 10.1016/j.freeradbiomed.2014.08.001
PMID: 25152236
PMCID: PMC4364304
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Grant note: name: DG, award: NCI-1R01CA152601-01, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA16383801A1, NIH R01 CA169046, NIH 5 P30 CA086862; DOI: 10.13039/100002135, name: Hirshberg Foundation for Pancreatic Cancer Research Seed; name: Weinberg of Northwestern University
Language: English
Date published: 11/2014
Academic Unit: Radiation Oncology
Record Identifier: 9984046900602771

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