Akt-mediated phosphorylation of MICU1 regulates mitochondrial Ca²⁺ levels and tumor growth

Although mitochondria play a multifunctional role in cancer progression and Ca²⁺ signaling is remodeled in a wide variety of tumors, the underlying mechanisms that link mitochondrial Ca²⁺ homeostasis with malignant tumor formation and growth remain elusive. Here, we show that phosphorylation at the N-terminal region of the mitochondrial calcium uniporter (MCU) regulatory subunit MICU1 leads to a notable increase in the basal mitochondrial Ca²⁺ levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion-targeted Akt strongly regulates the mitochondrial Ca²⁺ content. The Akt-mediated phosphorylation impairs MICU1 processing and stability, culminating in reactive oxygen species (ROS) production and tumor progression. Thus, our data reveal the crucial role of the Akt-MICU1 axis in cancer and underscore the strategic importance of the association between aberrant mitochondrial Ca²⁺ levels and tumor development.