Hypoxia-induced MT2A-tetrameric PKM2 interaction maintains PKM2 activity in a copper-ion-dependent manner

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Hypoxia is a hallmark of solid tumors associated with tumor malignancy. Mitochondrial metabolic reprogramming is a key step in the process of cellular adaptation to hypoxic stress for tumor growth, but the regulatory mechanisms are not fully understood. In this study, through mitochondrial proteomics analysis, we find that metallothionein-2A (MT2A) is top-ranked among the significantly upregulated proteins in mitochondrial extract in response to hypoxia. Further, we show that hypoxia can induce the mitochondrial translocation of MT2A, a process that is dependent on copper ion. MT2A is highly expressed in hypoxic tumor tissues compared to normoxic ones in breast cancer patients, among whom higher expression of MT2A is associated with a worse prognosis, and it is required for breast tumor growth. Mechanistically, we reveal that copper ion is also essential for hypoxia-induced mitochondrial translocation of Pyruvate kinase M2 (PKM2), and facilitates the interaction of MT2A with the tetrameric form of PKM2 to maintain its activity, thereby promoting glycolysis and oxidative phosphorylation. Thus, our findings reveal the MT2A-copper-PKM2 axis as a potential therapeutic target to treat breast cancer.