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Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression

Cell Research volume 33, pages 299–311 (2023)Cite this article

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Abstract

A well-established role of cyclic GMP-AMP synthase (cGAS) is the recognition of cytosolic DNA, which is linked to the activation of host defense programs against pathogens via stimulator of interferon genes (STING)-dependent innate immune response. Recent advance has also revealed that cGAS may be involved in several noninfectious contexts by localizing to subcellular compartments other than the cytosol. However, the subcellular localization and function of cGAS in different biological conditions is unclear; in particular, its role in cancer progression remains poorly understood. Here we show that cGAS is localized to mitochondria and protects hepatocellular carcinoma cells from ferroptosis in vitro and in vivo. cGAS anchors to the outer mitochondrial membrane where it associates with dynamin-related protein 1 (DRP1) to facilitate its oligomerization. In the absence of cGAS or DRP1 oligomerization, mitochondrial ROS accumulation and ferroptosis increase, inhibiting tumor growth. Collectively, this previously unrecognized role for cGAS in orchestrating mitochondrial function and cancer progression suggests that cGAS interactions in mitochondria can serve as potential targets for new cancer interventions.

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Fig. 1: cGAS is localized in mitochondria of cancer cells.
Fig. 2: Mitochondria-localized cGAS inhibits ferroptosis.
Fig. 3: Mitochondrial cGAS suppresses ferroptosis independent of STING activation.
Fig. 4: Mitochondrial cGAS associates with DRP1 and facilitates its oligomerization.
Fig. 5: Mitochondrial cGAS promotes tumor progression by suppressing ferroptosis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (91957203, 81930083, 82130087, 82072656, 82192893, 81821001), the National Key R&D Program of China (2018YFA0800303, 2022YFA1304504), the Chinese Academy of Sciences (XDB39000000), Hefei Comprehensive National Science Center Institute of Health and Medicine Project (DJK-LX-2022001).

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  1. These authors contributed equally: Shiqiao Qiu, Xiuying Zhong, Xiang Meng.

Authors and Affiliations

  1. School of Medicine, South China University of Technology, Guangzhou, Guangdong, China

    Shiqiao Qiu, Xiang Meng, Xiaoyu Qian, Jin Cai, Yi Zhang, Mingjie Wang, Zijian Ye & Ping Gao

  2. Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    Xiuying Zhong, Shiting Li & Ping Gao

  3. The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Hui Lu & Huafeng Zhang

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Contributions

P.G. conceived and supervised the study. X.Z., S.Q., P.G., and H.Z. designed the experiments. S.Q., X.Z., X.M., S.L., X.Q., H.L., J.C., Y.Z., M.W., and Z.Y. performed and analyzed the experiments. P.G., H.Z., X.Z., and S.Q. wrote the manuscript. All the authors read and approved the manuscript.

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Correspondence to Xiuying Zhong, Huafeng Zhang or Ping Gao.

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Qiu, S., Zhong, X., Meng, X. et al. Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression. Cell Res 33, 299–311 (2023). https://doi.org/10.1038/s41422-023-00788-1

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