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A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.
Jiang, Weiwei; Zhang, Mengyao; Gao, Chuan; Yan, Chaojun; Gao, Ronghui; He, Ziwei; Wei, Xin; Xiong, Jingjing; Ruan, Zilun; Yang, Qian; Li, Jinpeng; Li, Qifang; Zhong, Ziyi; Zhang, Mengna; Yuan, Qianqian; Hu, Hankun; Wang, Shuang; Hu, Ming-Ming; Cai, Cheguo; Wu, Gao-Song; Jiang, Chao; Zhang, Ya-Lin; Zhang, Chen-Song; Zhang, Jing.
Afiliación
  • Jiang W; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Zhang M; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Gao C; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Yan C; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Gao R; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • He Z; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Wei X; Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • Xiong J; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Ruan Z; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • Yang Q; Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Li J; Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Li Q; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Zhong Z; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Zhang M; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Yuan Q; Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Hu H; Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
  • Wang S; Mabnus Biological Technology Incorporation, Wuhan, China.
  • Hu MM; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • Cai C; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Wu GS; Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • Jiang C; Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • Zhang YL; State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, China.
  • Zhang CS; State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, China.
  • Zhang J; Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
EMBO J ; 42(20): e113743, 2023 10 16.
Article en En | MEDLINE | ID: mdl-37661833
Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Proteínas Quinasas Activadas por AMP Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: EMBO J Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Proteínas Quinasas Activadas por AMP Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: EMBO J Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido