Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex
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Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal growth factor (EGF)-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1, and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important in promoting glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.
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ACAT1 may drive acetylation of PDHA1 and PDP1 by associating with these proteins.
“In particular, acetyl-CoA acetyltransferase (ACAT1), which synthesizes acetoacetyl-CoA by condensing two molecules of acetyl-CoA as a precursor for ketone body synthesis, may be a driving source of acetylation of the pyruvate dehydrogenase complex component PDHA1 and its activating phosphatase PDP1 by associating with these proteins ((Fan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Fan et al. 2014
SIRT3 deacetylates PDP, enhancing its phosphatase activity on PDC and decreasing PDC phosphorylation.
“First, SIRT3 deacetylates K321 and second, SIRT3 also deacetylates PDP, enhancing its phosphatase activity on PDC and thereby decreasing PDC phosphorylation. ((Fan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Fan et al. 2014
SIRT3 deacetylates PDHA1 K321.
“First, SIRT3 deacetylates K321 and second, SIRT3 also deacetylates PDP, enhancing its phosphatase activity on PDC and thereby decreasing PDC phosphorylation. ((Fan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Fan et al. 2014
SIRT3 attenuation of reactive oxygen species production appears to inhibit a glycolytic shift in potentially cancerous cells.
“SIRT3’s attenuation of reactive oxygen species production appears to inhibit a glycolytic shift in potentially cancerous cells ((Finley et al. 2011); (Fan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Fan et al. 2014
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- Authors
- Fan, J., Shan, C., Kang, H.-B., Elf, S., Xie, J., Tucker, M., Gu, T.-L., Aguiar, M., Lonning, S., Chen, H., Mohammadi, M., Britton, L.-M. P., Garcia, B. A., Alečković, M., Kang, Y., Kaluz, S., Devi, N., Van Meir, E. G., Hitosugi, T., Seo, J. H., Lonial, S., Gaddh, M., Arellano, M., Khoury, H. J., Khuri, F. R., Boggon, T. J., Kang, S., & Chen, J.
- Affiliations
- Emory University (US)
- Cell Signaling Technology (United States) (US)
- New York University (US)
- Princeton University (US)
- University of Pennsylvania (US)
- Yale University (US)
- Corresponding author
- Chen, Jing
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 53
- Issue
- 4
- Pages
- 534-548
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3943932
- OpenAlex
- W2027522444
- Cited by
- 305
- References
- 33
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 29 · 2023: 30 · 2022: 24 · 2021: 37 · 2020: 24 · 2019: 17 · 2018: 25 · 2017: 22 · 2016: 25 · 2015: 22 · 2014: 16
- FWCI
- 12.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH-12-1-0217)
- National Institutes of Health (T32 GM008602, CA140515, CA116804)
- Georgia Cancer Coalition
- School of Medicine, Emory University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pyruvate dehydrogenase complex, PDP1, PDHA1, tyrosine phosphorylation, lysine acetylation, ACAT1, SIRT3, pyruvate dehydrogenase, Warburg effect, glycolysis, tumor growth, epidermal growth factor, post-translational modification, deacetylase
- MeSH terms
- Acetyl-CoA C-Acetyltransferase, Animals, Glycolysis, Humans, Lysine, Male, Mice, Nude, Mitochondria, Neoplasm Transplantation, Neoplasms, Phosphorylation, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Tyrosine, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Pyruvate Dehydrogenase (Lipoamide), Cell Line, Tumor, Cell Proliferation, Mice, Sirtuin 3
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