MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca 2+ Flux and Sensitivity to Ru360

Mol Cell. 2018 Nov 15;72(4):778-785.e3. doi: 10.1016/j.molcel.2018.09.008. Epub 2018 Oct 25.

Abstract

Proper control of the mitochondrial Ca2+ uniporter's pore (MCU) is required to allow Ca2+-dependent activation of oxidative metabolism and to avoid mitochondrial Ca2+ overload and cell death. The MCU's gatekeeping and cooperative activation is mediated by the Ca2+-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU's DIME motif, the selectivity filter. This led us to recognize in MICU1's sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter.

Keywords: Ca(2+) uptake; calcium signaling; cooperativity; mitochondria; oxidative stress; threshold.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Male
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Ruthenium Compounds / pharmacology*

Substances

  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • MICU1 protein, human
  • MICU1 protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Ru 360
  • Ruthenium Compounds
  • mitochondrial calcium uniporter
  • Calcium