Tyrosine Phosphorylation of Mitochondrial Pyruvate Dehydrogenase Kinase 1 Is Important for Cancer Metabolism

Taro Hitosugi, Jun Fan, Tae Wook Chung, Katherine Lythgoe, Xu Wang, Jianxin Xie, Qingyuan Ge, Ting Lei Gu, Roberto D. Polakiewicz, Johannes L. Roesel, Georgia Z. Chen, Titus J. Boggon, Sagar Lonial, Haian Fu, Fadlo R. Khuri, Sumin Kang, Jing Chen

Research output: Contribution to journalArticle

189 Scopus citations

Abstract

Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of the matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth.

Original languageEnglish (US)
Pages (from-to)864-877
Number of pages14
JournalMolecular Cell
Volume44
Issue number6
DOIs
StatePublished - Dec 23 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hitosugi, T., Fan, J., Chung, T. W., Lythgoe, K., Wang, X., Xie, J., Ge, Q., Gu, T. L., Polakiewicz, R. D., Roesel, J. L., Chen, G. Z., Boggon, T. J., Lonial, S., Fu, H., Khuri, F. R., Kang, S., & Chen, J. (2011). Tyrosine Phosphorylation of Mitochondrial Pyruvate Dehydrogenase Kinase 1 Is Important for Cancer Metabolism. Molecular Cell, 44(6), 864-877. https://doi.org/10.1016/j.molcel.2011.10.015