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

Abstract Although mitochondria play a multifunctional role in cancer progression and Ca 2+ signaling is remodeled in a wide variety of tumors, the underlying mechanisms that link mitochondrial Ca 2+ 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 2+ levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion‐targeted Akt strongly regulates the mitochondrial Ca 2+ 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 2+ levels and tumor development.