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

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 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 β2β3 loop region, suggesting a potential therapeutic target for breast cancer. © 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Citation

Weiwei Jiang, Mengyao Zhang, Chuan Gao, Chaojun Yan, Ronghui Gao, Ziwei He, Xin Wei, Jingjing Xiong, Zilun Ruan, Qian Yang, Jinpeng Li, Qifang Li, Ziyi Zhong, Mengna Zhang, Qianqian Yuan, Hankun Hu, Shuang Wang, Ming-Ming Hu, Cheguo Cai, Gao-Song Wu, Chao Jiang, Ya-Lin Zhang, Chen-Song Zhang, Jing Zhang. A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress. The EMBO journal. 2023 Oct 16;42(20):e113743

Mesh Tags

Substances

PMID: 37661833

search → result