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
  • 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.