RAC-alpha serine/threonine-protein kinase
protein serine/threonine kinase activity
Akt-mediated phosphorylation of MICU1 regulates mitochondrial Ca<sup>2+</sup> levels and tumor growth.
Although mitochondria play a multifunctional role in cancer progression and Ca<sup>2+</sup> signaling is remodeled in a wide variety of tumors, the underlying mechanisms that link mitochondrial Ca<sup>2+</sup> 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 Ca<sup>2+</sup> levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion-targeted Akt strongly regulates the mitochondrial Ca<sup>2+</sup> 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 Ca<sup>2+</sup> levels and tumor development.