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Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect

Oncogene volume 40, pages 6692–6702 (2021)Cite this article

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Abstract

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca2+-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.

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Fig. 1: Identification of PDHA1 and PDHB as calcineurin interactors.
Fig. 2: calcineurin dephosphorylates PDHA1.
Fig. 3: Calcineurin regulates PDC activity and oxidative phosphorylation.
Fig. 4: Mitochondrial-localized calcineurin inhibits tumor cell proliferation under hypoxia.
Fig. 5: CNIs modulate the mitochondrial OXPHOS.

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Acknowledgements

This work was supported by grants from the National Science Foundation of China (No. 91957125, 81972396 to CJW, No. 31330023, 3182100, 291753207, 31930062 to SMZ; No. 81722021, 81771627, 31521003 to JYZ; No. 31671483, 31871432 to WX), Shanghai Rising-Star Program (No. 18QA1400300 to WX), National Key R&D Program of China (No. 2018YFA0800300 to SMZ; 2019YFA0801900 to JYZ; 2018YFA0801300, 2018YFC1004700 to WX); Science and Technology Municipal Commission of Shanghai, China (No. 16JC1405301 to SMZ).

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Author notes

  1. These authors contributed equally: Jianong Zhang, Liang Zhang.

Authors and Affiliations

  1. Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Key Laboratory of Reproduction Regulation of NPFPC (SIPPR, IRD), School of Life Sciences, Fudan University, Shanghai, 200438, China

    Jianong Zhang, Liang Zhang, Ji Nie, Yan Lin, Yao Li, Shi-Min Zhao & Chenji Wang

  2. Shanghai Fifth People’s Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Wei Xu

  3. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Jian-Yuan Zhao

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CJW and SMZ and conceived the study. JNZ, LZ, and JN performed the experiments. JNZ, Yao L, Yan L, JYZ, and WX analyzed and interpreted the data. SMZ and CJW wrote and revised the paper.

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Correspondence to Shi-Min Zhao or Chenji Wang.

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Zhang, J., Zhang, L., Nie, J. et al. Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect. Oncogene 40, 6692–6702 (2021). https://doi.org/10.1038/s41388-021-02065-0

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