A mitochondrial EglN1‐AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress

• Published in: The EMBO journal 2023-10, Vol.42 (20), p.e113743-e113743
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adaptation; Binding; Breast cancer; Calcium ions; Calmodulin; Cell activation; Homeostasis; Hydroxylation; Hypoxia; Kinases; Malignancy; Metabolism; Mitochondria; Molecular modelling; Oxygen; Oxygen probes; Phosphorylation; Prolyl hydroxylase; Protein kinase; Proteins; Proteomics; Substrates; Therapeutic targets; Translocation; Tumors
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2023113743

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 β2β3 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 Ca 2+ /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 β2β3 loop region, suggesting a potential therapeutic target for breast cancer. image Mitochondria act as critical signaling hubs in cancer cells under hypoxic stress, but the molecular mechanisms involved remain poorly defined. This study identifies prolyl hydroxylase EglN1 (PHD2) as a mitochondrial oxygen sensor controlling AMPKα activation and cell metabolism under low oxygen conditions in mammary malignancies. EglN1 accumulates on mitochondria under hypoxia. EglN1 substrate‐binding β2β3 loop is required for mitochondrial translocation and breast cancer growth. EglN1 prolyl‐hydroxylates AMPKα on mitochondria. Hypoxia induces a EglN1‐CaMKK2‐AMPKα complex supporting AMPKα activation and cancer cell metabolism.