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Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria
| Content Provider | Scilit |
|---|---|
| Author | Hamilton, James Brustovetsky, Tatiana Rysted, Jacob E. Lin, Zhihong Usachev, Yuriy Brustovetsky, Nickolay |
| Copyright Year | 2018 |
| Description | Journal: Journal of Biological Chemistry $Ca^{2+}$ influx into mitochondria is mediated by the mitochondrial calcium uniporter (MCU), whose identity was recently revealed as a 40-kDa protein that along with other proteins forms the mitochondrial $Ca^{2+}$ uptake machinery. The MCU is a $Ca^{2+}$-conducting channel spanning the inner mitochondrial membrane. Here, deletion of the MCU completely inhibited $Ca^{2+}$ uptake in liver, heart, and skeletal muscle mitochondria. However, in brain nonsynaptic and synaptic mitochondria from neuronal somata/glial cells and nerve terminals, respectively, the MCU deletion slowed, but did not completely block, $Ca^{2+}$ uptake. Under resting conditions, brain MCU-KO mitochondria remained polarized, and in brain MCU-KO mitochondria, the electrophoretic $Ca^{2+}$ ionophore ETH129 significantly accelerated $Ca^{2+}$ uptake. The residual $Ca^{2+}$ uptake in brain MCU-KO mitochondria was insensitive to inhibitors of mitochondrial $Na^{+}/Ca^{2+}$ exchanger and ryanodine receptor (CGP37157 and dantrolene, respectively), but was blocked by the MCU inhibitor Ru360. Respiration of WT and MCU-KO brain mitochondria was similar except that for mitochondria that oxidized pyruvate and malate, $Ca^{2+}$ more strongly inhibited respiration in WT than in MCU-KO mitochondria. Of note, the MCU deletion significantly attenuated but did not completely prevent induction of the permeability transition pore (PTP) in brain mitochondria. Expression level of cyclophilin D and ATP content in mitochondria, two factors that modulate PTP induction, were unaffected by MCU-KO, whereas ADP was lower in MCU-KO than in WT brain mitochondria. Our results suggest the presence of an MCU-independent $Ca^{2+}$ uptake pathway in brain mitochondria that mediates residual $Ca^{2+}$ influx and induction of PTP in a fraction of the mitochondrial population. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177608/pdf http://www.jbc.org/content/293/40/15652.full.pdf |
| Ending Page | 15663 |
| Page Count | 12 |
| Starting Page | 15652 |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| DOI | 10.1074/jbc.ra118.002926 |
| Journal | Journal of Biological Chemistry |
| Issue Number | 40 |
| Volume Number | 293 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2018-10-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology Energy Metabolism Mitochondrial Membrane Potential Mitochondrial Permeability Transition (mpt) |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
