Volume 33, No 4, Apr 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 4, April 2023: 299-311

ORIGINAL ARTICLES

Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression

Shiqiao Qiu^1,† , Xiuying Zhong^2,†,* , Xiang Meng^1,† , Shiting Li² , Xiaoyu Qian¹ , Hui Lu³ , Jin Cai¹ , Yi Zhang¹ , Mingjie Wang¹ , Zijian Ye¹ , Huafeng Zhang^3,* , Ping Gao^1,2,*

¹School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
²Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
³The 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
^†These authors contributed equally: Shiqiao Qiu, Xiuying Zhong, Xiang Meng
Correspondence: Xiuying Zhong(zxywawj@ustc.edu.cn)Huafeng Zhang(hzhang22@ustc.edu.cn)Ping Gao(pgao2@ustc.edu.cn)

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.

https://doi.org/10.1038/s41422-023-00788-1

FULL TEXT | PDF

Browse 226