MICU2, a Paralog of MICU1, Resides Within the Mitochondrial Uniporter Complex to Regulate Calcium Handling

PLoS One. 2013;8(2):e55785. doi: 10.1371/journal.pone.0055785. Epub 2013 Feb 7.

Abstract

Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism*
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Respiration / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Liver / metabolism
  • Membrane Potential, Mitochondrial / genetics
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Multigene Family
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • Protein Stability
  • Protein Transport
  • RNA Interference
  • Sequence Alignment

Substances

  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • MICU1 protein, human
  • MICU2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • Multiprotein Complexes
  • Calcium