MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism.

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Mallilankaraman, Karthik | Cárdenas, César | Doonan, Patrick J | Chandramoorthy, Harish C | Irrinki, Krishna M | Golenár, Tünde | Csordás, György | Madireddi, Priyanka | Yang, Jun | Müller, Marioly | Miller, Russell | Kolesar, Jill E | Molgó, Jordi | Kaufman, Brett | Hajnóczky, György | Foskett, J Kevin | Madesh, Muniswamy

Edité par CCSD ; Nature Publishing Group -

International audience. Ca(2+) flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca(2+) signals and activation of cell death pathways. Mitochondrial Ca(2+) uptake occurs at regions of close apposition with intracellular Ca(2+) release sites, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca(2+) selective ion channel (MiCa; ref. ) called the uniporter whose complete molecular identity remains unknown. Mitochondrial calcium uniporter (MCU) was recently identified as the likely ion-conducting pore. In addition, MICU1 was identified as a mitochondrial regulator of uniporter-mediated Ca(2+) uptake in HeLa cells. Here we identified CCDC90A, hereafter referred to as MCUR1 (mitochondrial calcium uniporter regulator 1), an integral membrane protein required for MCU-dependent mitochondrial Ca(2+) uptake. MCUR1 binds to MCU and regulates ruthenium-red-sensitive MCU-dependent Ca(2+) uptake. MCUR1 knockdown does not alter MCU localization, but abrogates Ca(2+) uptake by energized mitochondria in intact and permeabilized cells. Ablation of MCUR1 disrupts oxidative phosphorylation, lowers cellular ATP and activates AMP kinase-dependent pro-survival autophagy. Thus, MCUR1 is a critical component of a mitochondrial uniporter channel complex required for mitochondrial Ca(2+) uptake and maintenance of normal cellular bioenergetics.

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