2. Academic Validation
  3. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter

MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter

  • Cell Metab. 2013 Jun 4;17(6):976-987. doi: 10.1016/j.cmet.2013.04.020.
György Csordás 1,  Tünde Golenár 1,  Erin L Seifert 1,  Kimberli J Kamer 2,  Yasemin Sancak 3,  Fabiana Perocchi 4,  Cynthia Moffat 1,  David Weaver 1,  Sergio de la Fuente Perez 1,  Roman Bogorad 5,  Victor Koteliansky 6,  Jeffrey Adijanto 1,  Vamsi K Mootha 7,  György Hajnóczky 8
Affiliations

Affiliations

  • 1 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • 2 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 3 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School and Broad Institute, Cambridge, MA 02142, USA.
  • 4 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School and Broad Institute, Cambridge, MA 02142, USA; Gene Center, Ludwig-Maximilians-Universität, Munich D-81377, Germany.
  • 5 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 6 Alnylam Pharmaceuticals Inc., Cambridge, MA 02142, USA.
  • 7 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School and Broad Institute, Cambridge, MA 02142, USA. Electronic address: [email protected].
  • 8 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: [email protected].
PMID: 23747253 DOI: 10.1016/j.cmet.2013.04.020
Abstract

Mitochondrial Ca(2+) uptake via the uniporter is central to cell metabolism, signaling, and survival. Recent studies identified MCU as the uniporter's likely pore and MICU1, an EF-hand protein, as its critical regulator. How this complex decodes dynamic cytoplasmic [Ca(2+)] ([Ca(2+)]c) signals, to tune out small [Ca(2+)]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca(2+) accumulation during small [Ca(2+)]c elevations but an attenuated response to agonist-induced [Ca(2+)]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca(2+)]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca(2+) binding, yet cells show impaired oxidative metabolism and sensitization to Ca(2+) overload. Collectively, the data indicate that MICU1 senses the [Ca(2+)]c to establish the uniporter's threshold and gain, thereby allowing mitochondria to properly decode different inputs.

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