Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex

Mol Cell. 2022 Oct 6;82(19):3661-3676.e8. doi: 10.1016/j.molcel.2022.09.006.


Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.

Keywords: calcium channels; cardiac pathophysiology; cellular metabolism; intracellular calcium signaling; membrane-transport mechanisms; mitochondrial physiology; mitochondrial proteases; organellar channels; protein complexes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Calcium Channels
  • Calcium* / metabolism
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / metabolism*
  • Disulfides / metabolism
  • Humans
  • Mice
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Reactive Oxygen Species / metabolism


  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • Disulfides
  • MICU1 protein, human
  • MICU1 protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Reactive Oxygen Species
  • mitochondrial calcium uniporter
  • Adenosine Triphosphate
  • Calcium