A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.
A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.
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DOI：
10.15252/embj.2023113743
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发表时间：
2023-10-16
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线粒体在癌细胞对缺氧的适应中起着重要作用，但其潜在机制仍不清楚。通过线粒体蛋白质组学分析，我们发现脯氨酰羟化酶EglN 1（PHD 2）在缺氧条件下在线粒体上积累。β2β3环中的EglN 1底物结合区负责其线粒体易位并有助于乳腺肿瘤生长。此外，我们确定AMP活化蛋白激酶α（AMPKα）作为线粒体上的EglN 1底物。EglN 1 ‐AMPKα相互作用对于它们的相互线粒体易位至关重要。EglN 1脯氨酰-羟化AMPKα后，在常氧条件下，它们在脯氨酰-羟化后迅速解离，导致它们立即从线粒体释放。相比之下，缺氧导致恒定的EglN 1-AMPKα相互作用及其在线粒体上的积累，导致形成Ca 2 +/钙调蛋白依赖性蛋白激酶2（CaMKK 2）-EglN 1-AMPKα复合物，以激活AMPKα磷酸化，确保代谢稳态和乳腺肿瘤生长。我们的研究结果将EglN 1确定为氧敏感的代谢检查点，通过其β2β3环区域向线粒体发出缺氧应激信号，这表明了乳腺癌的潜在治疗靶点。缺氧诱导的线粒体上EglN 1-CaMKK 2相互作用在乳腺癌生长期间保护AMPKα活化和代谢稳态。
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. Hypoxia‐induced EglN1‐CaMKK2 interaction on mitochondria safeguards AMPKα activation and metabolic homeostasis during breast cancer growth.
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