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PMID:20693986

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Citation

Perocchi, F, Gohil, VM, Girgis, HS, Bao, XR, McCombs, JE, Palmer, AE and Mootha, VK (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467:291-6

Abstract

Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.

Links

PubMed PMC2977980 Online version:10.1038/nature09358

Keywords

Allergens/chemistry; Allergens/genetics; Allergens/metabolism; Amino Acid Sequence; Antigens, Plant; Calcium/metabolism; Calcium Signaling; Calcium-Binding Proteins/chemistry; Calcium-Binding Proteins/deficiency; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism; Cation Transport Proteins; Cell Respiration; Cytoplasm/metabolism; DNA, Mitochondrial/analysis; EF Hand Motifs; Endoplasmic Reticulum/metabolism; Gene Knockdown Techniques; HeLa Cells; Homeostasis; Humans; Membrane Potentials; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins/chemistry; Mitochondrial Proteins/deficiency; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; NAD/metabolism; NADP/metabolism; Oxidative Phosphorylation; Protein Structure, Tertiary; Protein Transport; RNA Interference

Significance

Annotations

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

LEIMA:Q4QIT3

acts_upstream_of_or_within

GO:0055074: calcium ion homeostasis

ECO:0000266: sequence orthology evidence used in manual assertion

GeneDB:Tb927.8.1850

P

Seeded From UniProt

complete

TRYB2:Q581Z7

acts_upstream_of_or_within

GO:0055074: calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MICU1

located_in

GO:0005743: mitochondrial inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MICU1

part_of

GO:0005743: mitochondrial inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MICU1

involved_in

GO:0051560: mitochondrial calcium ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MICU1

involved_in

GO:0070509: calcium ion import

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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