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

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

Research output: Contribution to journalArticle

250 Scopus citations

Abstract

Ca2+ flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca2+ signals and activation of cell death pathways. Mitochondrial Ca2+ uptake occurs at regions of close apposition with intracellular Ca2+ release sites, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca2+ 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 Ca2+ uptake. MCUR1 binds to MCU and regulates ruthenium-red-sensitive MCU-dependent Ca2+ uptake. MCUR1 knockdown does not alter MCU localization, but abrogates Ca2+ 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 Ca2+ uptake and maintenance of normal cellular bioenergetics.

Original languageEnglish (US)
Pages (from-to)1336-1343
Number of pages8
JournalNature Cell Biology
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2012

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology

Cite this

Mallilankaraman, K., Cárdenas, C., Doonan, P. J., Chandramoorthy, H. C., Irrinki, K. M., Golenár, T., Csordás, G., Madireddi, P., Yang, J., Müller, M., Miller, R., Kolesar, J. E., Molgó, J., Kaufman, B., Hajnóczky, G., Foskett, J. K., & Madesh, M. (2012). MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nature Cell Biology, 14(12), 1336-1343. https://doi.org/10.1038/ncb2622