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Elevated mitochondrial SLC25A29 in cancer modulates metabolic status by increasing mitochondria-derived nitric oxide

Oncogene volume 37, pages 2545–2558 (2018)Cite this article

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Abstract

Warburg effect has been recognized as a hallmark of cancer cells for many years, but its modulation mechanism remains a great focus. Our current study found a member of solute carrier family 25 (SLC25A29), the main arginine transporter on mitochondria, significantly elevated in various cancer cells. Knockout of SLC25A29 by CRISPR/Cas9 inhibited proliferation and migration of cancer cells both in vitro and in vivo. SLC25A29-knockout cells also showed an altered metabolic status with enhanced mitochondrial respiration and reduced glycolysis. All of above impacts could be reversed after rescuing SLC25A29 expression in SLC25A29-knockout cells. Arginine is transported into mitochondria partly for nitric oxide (NO) synthesis. Deletion of SLC25A29 resulted in severe decrease of NO production, indicating that the mitochondria is a significant source of NO. SLC25A29-knockout cells dramatically altered the variation of metabolic processes, whereas addition of arginine failed to reverse the effect, highlighting the necessity of transporting arginine into mitochondria by SLC25A29. In conclusion, aberrant elevated SLC25A29 in cancer functioned to transport more arginine into mitochondria, improved mitochondria-derived NO levels, thus modulated metabolic status to facilitate increased cancer progression.

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Acknowledgements

This work is supported by the research grants held by Yuchun Gu (973 Project Number 2013CB531206, 973 Project Number 2012CB517803, and NSF Number 81170236 and Number 31127001).

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China

    Huiyuan Zhang, Qinyi Wang, Junzhong Gu, Le Yin, Shenghui Liang, Lida Wu, Hao Xu & Yuchun Gu

  2. Department of Clinical Neurosciences, WT-MRC Cambridge Stem Cell Institute, Cambridge University, Cambridge, UK

    Chao Zhao

  3. Translational and Regenerative Medicine Center, Aston Medical Research Institute, Aston University, Birmingham, UK

    Yuchun Gu

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  1. Huiyuan Zhang
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Zhang, H., Wang, Q., Gu, J. et al. Elevated mitochondrial SLC25A29 in cancer modulates metabolic status by increasing mitochondria-derived nitric oxide. Oncogene 37, 2545–2558 (2018). https://doi.org/10.1038/s41388-018-0139-x

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