The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter
Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69312 |
| _version_ | 1811180488013905920 |
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| author | Vivek Garg Junji Suzuki Ishan Paranjpe Tiffany Unsulangi Liron Boyman Lorin S Milescu W Jonathan Lederer Yuriy Kirichok |
| author_facet | Vivek Garg Junji Suzuki Ishan Paranjpe Tiffany Unsulangi Liron Boyman Lorin S Milescu W Jonathan Lederer Yuriy Kirichok |
| author_sort | Vivek Garg |
| collection | DOAJ |
| description | Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the intermembrane space. Here, we provide rigorous analysis of Ca2+ and Na+ fluxes via MCUcx in intact isolated mitochondria to understand the function of MICU subunits. We also perform direct patch clamp recordings of macroscopic and single MCUcx currents to gain further mechanistic insights. This comprehensive analysis shows that the MCUcx pore, composed of the EMRE and MCU subunits, is not occluded nor plugged by MICUs during the absence or presence of extramitochondrial Ca2+ as has been widely reported. Instead, MICUs potentiate activity of MCUcx as extramitochondrial Ca2+ is elevated. MICUs achieve this by modifying the gating properties of MCUcx allowing it to spend more time in the open state. |
| first_indexed | 2024-04-11T09:03:57Z |
| format | Article |
| id | doaj.art-969b8933d4d94f3b855e9debf3b71deb |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:03:57Z |
| publishDate | 2021-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-969b8933d4d94f3b855e9debf3b71deb2022-12-22T04:32:42ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.69312The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporterVivek Garg0https://orcid.org/0000-0002-6940-5415Junji Suzuki1Ishan Paranjpe2Tiffany Unsulangi3Liron Boyman4Lorin S Milescu5W Jonathan Lederer6Yuriy Kirichok7https://orcid.org/0000-0001-7155-843XDepartment of Physiology, University of California San Francisco, San Francisco, United States; Department of Physiology, University of Maryland, Baltimore, United StatesDepartment of Physiology, University of California San Francisco, San Francisco, United StatesDepartment of Physiology, University of California San Francisco, San Francisco, United StatesDepartment of Physiology, University of California San Francisco, San Francisco, United StatesDepartment of Physiology, University of Maryland, Baltimore, United StatesDepartment of Biology, University of Maryland, College Park, United StatesDepartment of Physiology, University of Maryland, Baltimore, United StatesDepartment of Physiology, University of California San Francisco, San Francisco, United StatesCa2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the intermembrane space. Here, we provide rigorous analysis of Ca2+ and Na+ fluxes via MCUcx in intact isolated mitochondria to understand the function of MICU subunits. We also perform direct patch clamp recordings of macroscopic and single MCUcx currents to gain further mechanistic insights. This comprehensive analysis shows that the MCUcx pore, composed of the EMRE and MCU subunits, is not occluded nor plugged by MICUs during the absence or presence of extramitochondrial Ca2+ as has been widely reported. Instead, MICUs potentiate activity of MCUcx as extramitochondrial Ca2+ is elevated. MICUs achieve this by modifying the gating properties of MCUcx allowing it to spend more time in the open state.https://elifesciences.org/articles/69312mouse embryonic fibroblastsmitochondrial calcium uniportermitochondriaion channelspatch clampcalcium signaling |
| spellingShingle | Vivek Garg Junji Suzuki Ishan Paranjpe Tiffany Unsulangi Liron Boyman Lorin S Milescu W Jonathan Lederer Yuriy Kirichok The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter eLife mouse embryonic fibroblasts mitochondrial calcium uniporter mitochondria ion channels patch clamp calcium signaling |
| title | The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter |
| title_full | The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter |
| title_fullStr | The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter |
| title_full_unstemmed | The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter |
| title_short | The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter |
| title_sort | mechanism of micu dependent gating of the mitochondrial ca2 uniporter |
| topic | mouse embryonic fibroblasts mitochondrial calcium uniporter mitochondria ion channels patch clamp calcium signaling |
| url | https://elifesciences.org/articles/69312 |
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