Review Article | Published:

The molecular era of the mitochondrial calcium uniporter

Nature Reviews Molecular Cell Biology volume 16, pages 545553 (2015) | Download Citation

Abstract

The mitochondrial calcium uniporter is an evolutionarily conserved calcium channel, and its biophysical properties and relevance to cell death, bioenergetics and signalling have been investigated for decades. However, the genes encoding this channel have only recently been discovered, opening up a new 'molecular era' in the study of its biology. We now know that the uniporter is not a single protein but rather a macromolecular complex consisting of pore-forming and regulatory subunits. We review recent studies that harnessed the power of molecular biology and genetics to characterize the mechanism of action of the uniporter, its evolution and its contribution to physiology and human disease.

Key points

  • The molecular identity of the human mitochondrial calcium uniporter has now been elucidated using integrative genomics. The mammalian uniporter is a protein complex consisting of the inner membrane-spanning subunits mitochondrial calcium uniporter protein (MCU), MCUb and essential MCU regulator (EMRE), together with mitochondrial calcium uptake protein 1 (MICU1) and MICU2 in the intermembrane space.

  • Expression of human MCU and EMRE is sufficient to reconstitute uniporter pore activity in vivo.

  • MICU1 and MICU2 operate together in the intermembrane space to sense calcium concentration and regulate the uniporter.

  • Loss of uniporter activity can be tolerated in vivo in organisms including trypanosomes, worms and mice.

  • Genetic studies in cells and in model organisms are converging on a key function for this channel in the coupling of cellular ATP consumption with its production (termed excitation–energetic coupling). The role of the channel in cell death and apoptosis remains controversial.

  • Inherited mutations in the uniporter machinery have been identified in patients with neuromuscular disease.

  • Next steps include using structural biology to gain mechanistic insights into the uniporter and investigating pathologies associated with the manipulation of uniporter activity, which may suggest a therapeutic strategy for targeting the uniporter.

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Author information

Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Kimberli J. Kamer
  2. Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street 6th Floor, Boston, Massachusetts 02114, USA.

    • Kimberli J. Kamer
    •  & Vamsi K. Mootha
  3. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Vamsi K. Mootha
  4. Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Vamsi K. Mootha

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vamsi K. Mootha.

Glossary

Mitoplast

A mitochondrion without the outer membrane.

EF hand

A calcium-binding motif consisting of a helix–loop–helix structure.

Excitation–energetic coupling

The coupling of cellular ATP consumption with its production.

Leukotriene receptor

A receptor that is present in immune cells, which can be activated by leukotrienes to lead to an inflammatory cascade.

Store-operated calcium entry

(SOCE). A mechanism to replenish endoplasmic reticulum calcium stores, which occurs through calcium release-activated channels in the plasma membrane.

NLRP3 inflammasome

A large protein complex that is part of the innate immune system; it can be activated by many different stimuli to trigger inflammatory processes.

Tricarboxylic acid (TCA) cycle

A series of enzymatic reactions in the mitochondrial matrix that take acetyl coenzyme A through a series of oxidation steps, which are important for many biosynthetic pathways and also produce reducing equivalents to feed into the respiratory chain. Two enzymes in the TCA cycle, α-ketoglutarate dehydrogenase and isocitrate dehydrogenase, are activated by matrix calcium ions.

Skeletal muscle myopathy

A disorder of skeletal muscle that can manifest as weakness, cramps or exercise intolerance.

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DOI

https://doi.org/10.1038/nrm4039

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