Journal article
Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria
The Journal of biological chemistry, Vol.293(40), pp.15652-15663
10/05/2018
DOI: 10.1074/jbc.RA118.002926
PMCID: PMC6177608
PMID: 30154242
Abstract
Ca2+ 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 Ca2+ uptake machinery. The MCU is a Ca2+-conducting channel spanning the inner mitochondrial membrane. Here, deletion of the MCU completely inhibited Ca2+ 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, Ca2+ uptake. Under resting conditions, brain MCU-KO mitochondria remained polarized, and in brain MCU-KO mitochondria, the electrophoretic Ca2+ ionophore ETH129 significantly accelerated Ca2+ uptake. The residual Ca2+ uptake in brain MCU-KO mitochondria was insensitive to inhibitors of mitochondrial Na+/Ca2+ 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, Ca2+ 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 Ca2+ uptake pathway in brain mitochondria that mediates residual Ca2+ influx and induction of PTP in a fraction of the mitochondrial population.
Details
- Title: Subtitle
- Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria
- Creators
- James Hamilton - From the Department of Pharmacology and Toxicology and Indiana University School of Medicine, Indianapolis, Indiana 46202Tatiana Brustovetsky - From the Department of Pharmacology and Toxicology and Indiana University School of Medicine, Indianapolis, Indiana 46202Jacob E Rysted - the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Zhihong Lin - the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Yuriy M Usachev - the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Nickolay Brustovetsky - From the Department of Pharmacology and Toxicology and Indiana University School of Medicine, Indianapolis, Indiana 46202
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(40), pp.15652-15663
- DOI
- 10.1074/jbc.RA118.002926
- PMID
- 30154242
- PMCID
- PMC6177608
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- Indiana Traumatic Spinal Cord & Brain injury Research Fund
- Language
- English
- Date published
- 10/05/2018
- Academic Unit
- Neurology; Iowa Neuroscience Institute; Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984070259302771
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