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Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits

Oncogene volume 38, pages 6926–6939 (2019)Cite this article

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Abstract

Tumor mitochondria have heightened protein folding quality control, but the regulators of this process and how they impact cancer traits are not completely understood. Here we show that the ATP-directed mitochondrial protease, LonP1 is upregulated by stress conditions, including hypoxia, in tumor, but not normal cells. In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. Interference with this pathway induces accumulation of misfolded subunits of electron transport chain complex II and complex V, resulting in impaired oxidative bioenergetics and heightened ROS production. Functionally, this suppresses mitochondrial trafficking to the cortical cytoskeleton, shuts off tumor cell migration and invasion, and inhibits primary and metastatic tumor growth, in vivo. These data identify LonP1 as a key effector of mitochondrial reprogramming in cancer and potential therapeutic target.

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Acknowledgements

We thank James Hayden and Frederick Keeney for assistance with time-lapse videomicroscopy and Sandra Harper for performing the HPLC gel filtration experiments. This work was supported by the National Institutes of Health (NIH) grants P01 CA140043 (DCA and DWS), R35 CA220446 (D.C.A.) R50 CA221838 (H-YT), and R50 CA211199 (AVK). and Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute.

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Authors and Affiliations

  1. Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA

    Jagadish C. Ghosh, Jae Ho Seo, Ekta Agarwal, Yuan Wang, David W. Speicher & Dario C. Altieri

  2. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA

    Jagadish C. Ghosh, Jae Ho Seo, Ekta Agarwal, Yuan Wang & Dario C. Altieri

  3. Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA, 19104, USA

    Andrew V. Kossenkov, Hsin-Yao Tang & David W. Speicher

  4. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104, USA

    David W. Speicher

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Ghosh, J.C., Seo, J.H., Agarwal, E. et al. Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits. Oncogene 38, 6926–6939 (2019). https://doi.org/10.1038/s41388-019-0939-7

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