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.

Akt-mediated phosphorylation of MICU1 regulates mitochondrial Ca 2+ levels and tumor growth

Marchi, Saverio
Primo
;
Corricelli, Mariangela
Secondo
;
Branchini, Alessio;VITTO, VERONICA ANGELA MARIA;Missiroli, Sonia;Morciano, Giampaolo;Perrone, Mariasole;Ferrarese, Mattia;Giorgi, Carlotta;Pinotti, Mirko;Pinton, Paolo
Ultimo
2019

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.
Marchi, Saverio; Corricelli, Mariangela; Branchini, Alessio; Vitto, VERONICA ANGELA MARIA; Missiroli, Sonia; Morciano, Giampaolo; Perrone, Mariasole; Ferrarese, Mattia; Giorgi, Carlotta; Pinotti, Mirko; Galluzzi, Lorenzo; Kroemer, Guido; Pinton, Paolo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2397092
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