| First Author | Hamilton J | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 40 | Pages | 15652-15663 |
| PubMed ID | 30154242 | Mgi Jnum | J:272829 |
| Mgi Id | MGI:6268598 | Doi | 10.1074/jbc.RA118.002926 |
| Citation | Hamilton J, et al. (2018) Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria. J Biol Chem 293(40):15652-15663 |
| abstractText | 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. |
