The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells
Mitochondrial Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>M</sub>) uptake through its Ca<sup>2+</sup> uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca<sup>2+</sup> signals, and apoptosis....
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| Format: | Article |
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MDPI AG
2020-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/6/1520 |
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| author | Syed Islamuddin Shah Ghanim Ullah |
| author_facet | Syed Islamuddin Shah Ghanim Ullah |
| author_sort | Syed Islamuddin Shah |
| collection | DOAJ |
| description | Mitochondrial Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>M</sub>) uptake through its Ca<sup>2+</sup> uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca<sup>2+</sup> signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca<sup>2+</sup> influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>C</sub>), [Ca<sup>2+</sup>]<sub>M</sub>, and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca<sup>2+</sup> buffering proteins, the separation between mitochondrion and Ca<sup>2+</sup>-releasing stores, and the duration of opening of Ca<sup>2+</sup>-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU. |
| first_indexed | 2024-03-10T18:58:12Z |
| format | Article |
| id | doaj.art-5a58d0512a7342eda7e7b8ed9738f631 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T18:58:12Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-5a58d0512a7342eda7e7b8ed9738f6312023-11-20T04:35:41ZengMDPI AGCells2073-44092020-06-0196152010.3390/cells9061520The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO CellsSyed Islamuddin Shah0Ghanim Ullah1Department of Physics, University of South Florida, Tampa, FL 33647, USADepartment of Physics, University of South Florida, Tampa, FL 33647, USAMitochondrial Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>M</sub>) uptake through its Ca<sup>2+</sup> uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca<sup>2+</sup> signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca<sup>2+</sup> influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>C</sub>), [Ca<sup>2+</sup>]<sub>M</sub>, and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca<sup>2+</sup> buffering proteins, the separation between mitochondrion and Ca<sup>2+</sup>-releasing stores, and the duration of opening of Ca<sup>2+</sup>-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU.https://www.mdpi.com/2073-4409/9/6/1520mitochondrial Ca<sup>2+</sup> uptakemitochondrial Ca<sup>2+</sup> uniporterMICU1MICU2EMRECa<sup>2+</sup> overload |
| spellingShingle | Syed Islamuddin Shah Ghanim Ullah The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells Cells mitochondrial Ca<sup>2+</sup> uptake mitochondrial Ca<sup>2+</sup> uniporter MICU1 MICU2 EMRE Ca<sup>2+</sup> overload |
| title | The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells |
| title_full | The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells |
| title_fullStr | The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells |
| title_full_unstemmed | The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells |
| title_short | The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells |
| title_sort | function of mitochondrial calcium uniporter at the whole cell and single mitochondrion levels in wt micu1 ko and micu2 ko cells |
| topic | mitochondrial Ca<sup>2+</sup> uptake mitochondrial Ca<sup>2+</sup> uniporter MICU1 MICU2 EMRE Ca<sup>2+</sup> overload |
| url | https://www.mdpi.com/2073-4409/9/6/1520 |
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