2. Academic Validation
  3. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity

MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity

  • Mol Cell. 2014 Mar 6;53(5):726-37. doi: 10.1016/j.molcel.2014.01.013.
Maria Patron 1,  Vanessa Checchetto 2,  Anna Raffaello 1,  Enrico Teardo 2,  Denis Vecellio Reane 1,  Maura Mantoan 1,  Veronica Granatiero 1,  Ildikò Szabò 2,  Diego De Stefani 3,  Rosario Rizzuto 4
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy.
  • 2 Department of Biology, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy.
  • 3 Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy. Electronic address: diego.destefani@gmail.com.
  • 4 Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy. Electronic address: rosario.rizzuto@unipd.it.
PMID: 24560927 DOI: 10.1016/j.molcel.2014.01.013
Abstract

Mitochondrial calcium accumulation was recently shown to depend on a complex composed of an inner-membrane channel (MCU and MCUb) and regulatory subunits (MICU1, MCUR1, and EMRE). A fundamental property of MCU is low activity at resting cytosolic CA(2+) concentrations, preventing deleterious CA(2+) cycling and organelle overload. Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. Both MICU1 and MICU2 are regulated by calcium through their EF-hand domains, thus accounting for the sigmoidal response of MCU to [CA(2+)] in situ and allowing tight physiological control. At low [CA(2+)], the dominant effect of MICU2 largely shuts down MCU activity; at higher [CA(2+)], the stimulatory effect of MICU1 allows the prompt response of mitochondria to CA(2+) signals generated in the cytoplasm.

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