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PMID:24560927

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Citation

Patron, M, Checchetto, V, Raffaello, A, Teardo, E, Vecellio Reane, D, Mantoan, M, Granatiero, V, Szabò, I, De Stefani, D and Rizzuto, R (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol. Cell 53:726-37

Abstract

Mitochondrial calcium accumulation was recently shown to depend on a complex composed of an inner-membrane channel (MCU and MCUb) and regulatory subunits (MICU1, MCUR1, and EMRE). A fundamental property of MCU is low activity at resting cytosolic Ca(2+) concentrations, preventing deleterious Ca(2+) cycling and organelle overload. Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. Both MICU1 and MICU2 are regulated by calcium through their EF-hand domains, thus accounting for the sigmoidal response of MCU to [Ca(2+)] in situ and allowing tight physiological control. At low [Ca(2+)], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca(2+)], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca(2+) signals generated in the cytoplasm.

Links

PubMed PMC3988891 Online version:10.1016/j.molcel.2014.01.013

Keywords

Aequorin/chemistry; Calcium/chemistry; Calcium Channels/metabolism; Calcium-Binding Proteins/metabolism; Cation Transport Proteins/metabolism; Cytoplasm/metabolism; Cytosol/metabolism; Dimerization; Disulfides; Electrophysiology/methods; Gene Expression Regulation; Gene Silencing; HeLa Cells; Humans; Immunohistochemistry; Lipid Bilayers/chemistry; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins/metabolism; Protein Binding; RNA, Small Interfering/metabolism; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MICU2

enables

GO:0005509: calcium ion binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MICU2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8VCX5

F

Seeded From UniProt

complete

MOUSE:MICU2

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8VCX5

F

Seeded From UniProt

complete

HUMAN:MICU2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BPX6

F

Seeded From UniProt

complete

HUMAN:MICU2

part_of

GO:1990246: uniplex complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MICU2

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MICU2

involved_in

GO:0006851: mitochondrial calcium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MICU2

involved_in

GO:0051562: negative regulation of mitochondrial calcium ion concentration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MICU2

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BPX6

F

Seeded From UniProt

complete

MOUSE:MICU1

enables

GO:0005509: calcium ion binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MICU1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CD10

F

Seeded From UniProt

complete

MOUSE:MICU1

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CD10

F

Seeded From UniProt

complete

HUMAN:MICU1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IYU8

F

Seeded From UniProt

complete

HUMAN:MICU1

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MICU1

part_of

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MICU1

involved_in

GO:0006851: mitochondrial calcium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MICU1

enables

GO:0046982: protein heterodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IYU8

F

Seeded From UniProt

complete

HUMAN:MICU1

involved_in

GO:0051561: positive regulation of mitochondrial calcium ion concentration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MICU1

part_of

GO:1990246: uniplex complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MCU

enables

GO:0015292: uniporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MCU

involved_in

GO:0006851: mitochondrial calcium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MCU

enables

GO:0005262: calcium channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MCU

involved_in

GO:0051561: positive regulation of mitochondrial calcium ion concentration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MCU

part_of

GO:1990246: uniplex complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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