Journal
EMBO JOURNAL
Volume 38, Issue 2, Pages -Publisher
WILEY
DOI: 10.15252/embj.201899435
Keywords
Akt; calcium; cancer; MICU1; mitochondria
Categories
Funding
- Telethon [GGP15219/B]
- Italian Association for Cancer Research [AIRC: IG-19803, AIRC: IG-18624]
- University of Ferrara
- Fondazione Umberto Veronesi
- Italian Ministry of Health [GR-2013-02356747, GR-2016-02364602]
- Fondazione Cariplo grant
- Ligue Contre le Cancer Comite de Charente-Maritime (Equipe Labelisee)
- Agence National de la Recherche (ANR)-Projets Blancs
- ANR Under the Frame of E-Rare-2
- ERA-Net for Research on Rare Diseases
- Association pour la Recherche sur le Cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Institut Universitaire de France
- Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
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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.
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