Mitochondria EglN1 drivers breast cancer progression by controlling metabolic adatation to hypoxic stress
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ABSTRACT: Hypoxia is a hallmark of solid tumors. Mitochondria play essential roles in cellular adaptation to hypoxia, but the underlying mechanisms are not fully understood. Through mitochondrial proteomic profiling, we find that the prolyl hydroxylase EglN1 accumulates on mitochondria under hypoxia. EglN1 substrate binding region 23 loop is responsible for its mitochondrial translocation and contributes to tumor growth. Furthermore, we identify AMPK as an EglN1 substrate on mitochondria. The EglN1-AMPK interaction is essential for their mutual mitochondrial translocation. EglN1 prolyl-hydroxylates AMPK under normoxia, then they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. While hypoxia results in constant EglN1-AMPK interaction and accumulation on mitochondria, leading to the formation of CaMKK2-EglN1-AMPK complex to activate AMPK phosphorylation, consequently ensuring metabolic homeostasis and tumor growth. Our findings demonstrate EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its 23 loop, revealing a therapeutic target for solid tumors.
INSTRUMENT(S): LTQ Orbitrap
ORGANISM(S): Homo Sapiens (human)
DISEASE(S): Chronic Bronchitis,Breast Cancer
SUBMITTER: gao chuan
LAB HEAD: Jing Zhang
PROVIDER: PXD041653 | Pride | 2023-08-29
REPOSITORIES: Pride
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