title: MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter.
abstract: The mitochondrial uniporter is a selective Ca(2+) channel regulated by MICU1, an EF hand-containing protein in the organelle's intermembrane space. MICU1 physically associates with and is co-expressed with a paralog, MICU2. To clarify the function of MICU1 and its relationship to MICU2, we used gene knockout (KO) technology. We report that HEK-293T cells lacking MICU1 or MICU2 lose a normal threshold for Ca(2+) intake, extending the known gating function of MICU1 to MICU2. Expression of MICU1 or MICU2 mutants lacking functional Ca(2+)-binding sites leads to a striking loss of Ca(2+) uptake, suggesting that MICU1/2 disinhibit the channel in response to a threshold rise in [Ca(2+)]. MICU2's activity and physical association with the pore require the presence of MICU1, though the converse is not true. We conclude that MICU1 and MICU2 are nonredundant and together set the [Ca(2+)] threshold for uniporter activity.
authors: Department of Molecular Biology, Howard Hughes Medical Institute Massachusetts General Hospital, Boston, MA, USA.
authors: Kimberli J
authors: KJ
authors: Kamer
authors: Vamsi K
authors: VK
authors: Mootha
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; C582650:MICU2 protein, human; D033681:Mitochondrial Membrane Transport Proteins; C034703:mitochondrial calcium uniporter; D002118:Calcium