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ATHENA promotes the assembly of the ATP synthase-associated macromolecular complex and cancer progression
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DOI：10.1038/s41418-026-01840-4.png)
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Abstract
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The ATP synthase-associated macromolecular complex plays a crucial role in cellular energy homeostasis. However, the regulation and potential function of this complex remain poorly understood in cancer. Here, we identify a 170-amino acid protein encoded by the lncRNA LINC00528, which we term ATP synthase-associated macromolecular complex enhancing microprotein (ATHENA). Mechanistically, ATHENA localizes to the mitochondrial inner membrane, in which ATHENA directly interacts with ATP synthase subunits (β and γ) and solute carrier proteins, including ANT and PiC, thereby promoting the assembly of these macromolecular complexes, enhancing ATP synthesis, and preserving mitochondrial and cristae architecture. Functionally, ATHENA promotes the proliferation, migration, and invasion of renal cell carcinoma (RCC) cells in vitro and drives RCC tumor growth and metastasis in vivo. Clinically, ATHENA is upregulated in RCC tissues and associated with poorer prognosis in RCC patients. Collectively, our findings identify ATHENA as a previously unrecognized mitochondrial microprotein that facilitates the assembly of ATP synthase-associated macromolecular complex and drives RCC progression.
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