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The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter

Charles B Phillips1, Chen-Wei Tsai1,2, Ming-Feng Tsai1,2

  • 1Department of Biochemistry, Brandeis University, Waltham, United States.

Elife
|January 15, 2019
PubMed

Insights

The mitochondrial calcium uniporter

Area of Science:

  • Mitochondrial biology
  • Ion channel regulation
  • Cellular signaling

Background:

  • The mitochondrial calcium uniporter (MCU) regulates cellular calcium homeostasis, impacting oxidative phosphorylation and apoptosis.
  • The MCU complex comprises pore-forming MCU protein and regulatory subunits (EMRE, MICU1, MICU2).
  • Ca2+-dependent activation of the MCU, mediated by MICU subunits, is crucial for its function but poorly understood.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying Ca2+-dependent gating of the mitochondrial calcium uniporter.
  • To investigate the interaction between the MCU pore-forming protein and regulatory MICU subunits.

Main Methods:

  • Site-directed mutagenesis of MICU1 and MCU proteins.
  • Biochemical assays to assess protein interactions.
  • Functional assays measuring mitochondrial Ca2+ flux.

Main Results:

  • The DIME aspartate in MCU forms a Ca2+-modulated electrostatic interaction with MICU1.
  • A specific interface between MCU and MICU1 involves a Ser residue at the pore entrance.
  • Mutagenesis identified two conserved Arg residues in MICU1 critical for MCU interaction.
  • Disruption of MCU-MICU1 interaction leads to unregulated mitochondrial Ca2+ influx.

Conclusions:

  • MICU1 acts as a gatekeeper for the mitochondrial calcium uniporter.
  • Ca2+ binding to MCU-MICU1 interfaces regulates channel activity by blocking or unblocking the MCU pore.
  • This interaction is essential for maintaining physiological Ca2+ signaling and preventing aberrant mitochondrial Ca2+ uptake.
Keywords:
biochemistrychemical biologyintracellular calcium signalingion channelsmembrane transportmitochondrial calciummitochondrial physiologymolecular biophysicsnonestructural biology

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