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.

Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Marchi, S., Corricelli, M., Branchini, A., Vitto, V. A. M., Missiroli, S., Morciano, G., Perrone, M., Ferrarese, M., Giorgi, C., Pinotti, M., Galluzzi, L., Kroemer, G., Pinton, P. Tags: Cancer, Membrane & Intracellular Transport Articles Source Type: research