期刊
EMBO REPORTS
卷 15, 期 3, 页码 299-307出版社
WILEY
DOI: 10.1002/embr.201337946
关键词
mitochondria; uniporter; calcium; MICU1; MICU2
资金
- National Science Foundation
- National Institutes of Health [DK080261]
Abstract The mitochondrial uniporter is a selective Ca2+ 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 Ca2+ intake, extending the known gating function of MICU1 to MICU2. Expression of MICU1 or MICU2 mutants lacking functional Ca2+-binding sites leads to a striking loss of Ca2+ uptake, suggesting that MICU1/2 disinhibit the channel in response to a threshold rise in [Ca2+]. 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 [Ca2+] threshold for uniporter activity. Synopsis image The mitochondrial calcium uniporter is regulated by MICU1 and MICU2. Using gene knockouts, Ca2+ physiology, and biochemistry, this study shows that MICU1 and MICU2 operate together, with nonredundant roles, in inhibiting Ca2+ uptake when cytosolic [Ca2+] is below threshold, but permitting transport when [Ca2+] rises. MICU1 and MICU2 play nonredundant roles in preventing mitochondrial calcium uptake via MCU when outside calcium is low MICU1 and MICU2 permit calcium uptake in response to a stimulus above the threshold.
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