)| PMID |
14660707 ( ) |
|---|---|
| Title | Impact of mitochondrial inhibition on excitability and cytosolic Ca2+ levels in brainstem motoneurones from mouse. |
| Abstract | Motoneurones (MNs) are particularly affected by the inhibition of mitochondrial metabolism, which has been linked to their selective vulnerability during pathophysiological states like hypoxia and amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To elucidate underlying events, we used sodium cyanide (CN) as a pharmacological inhibitor of complex IV of the mitochondrial respiratory chain ('chemical hypoxia') and investigated the cellular response in vulnerable and resistant neurone types. Bath application of 2 mm CN activated TTX-insensitive Na+ conductances in vulnerable hypoglossal MNs, which depolarized these MNs by 10.2 +/- 1.1 mV and increased their action potential activity. This response was mimicked by sodium azide (2 mm) and largely prevented by preincubation with the antioxidants ascorbic acid (1 mm) and Trolox (750 microm), indicating an involvement of reactive oxygen species (ROS) in the activation mechanism. CN also elevated cytosolic [Ca2+] levels through (i) Ca2+ release from mitochondria-controlled stores, (ii) significant retardation of cytosolic Ca2+ clearance rates, even when cytosolic ATP levels were held constant during whole-cell recording, and (iii) secondary Ca2+ influx during elevated firing rates. Blocking mitochondrial ATP production additionally raised cytosolic Ca2+ levels and prolonged recovery of Ca2+ transients with a delay of 5-6 min. Comparative studies on hypoglossal MNs, facial MNs and dorsal vagal neurones suggested that CN responses were dominated by the activation of K+ conductances in resistant neurones, thus reducing excitability during mitochondrial inhibition. In summary, our observations therefore support a model where selective MN vulnerability results from a synergistic accumulation of risk factors, including low cytosolic Ca2+ buffering, strong mitochondrial impact on [Ca2+]i, and a mitochondria-controlled increase in electrical excitability during metabolic disturbances. Humboldtallee 23, Germany. |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 3 | SOD1 | |
| 12680 | VEGFA | vascular endothelial growth factor A | 2 | VEGF | vascular endothelial growth factor | |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | 2 | cytochrome c oxidase | |
| 6893 | MAPT | microtubule-associated protein tau | 1 | tau | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 6893 | MAPT | microtubule-associated protein tau | tau | 0.3 | 2 transients was assessed by determining the recovery time constant tau (_amp_#x003c4;) _amp_#x003c4 after fitting with a single-exponential function |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.1 | inhibition are paralleled by observations in cell lines expressing mutant SOD1 which show increased basal Ca 2 loads ( Carri et |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.1 | resemble increased Na currents and enhanced neuronal excitability in mutant SOD1 mouse spinal MNs ( Kuo et al 2002 2003 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.1 | by a mutated Cu/Zn Cu Zn super oxide dismutase (SOD1) SOD1 is thought to be causally involved in MN degeneration ( |
| 12680 | VEGFA | vascular endothelial growth factor A | VEGF | 2.8 | on the observation that impaired vascular endothelial growth factor (VEGF) VEGF synthesis due to hypoxia selectively damages MNs ( Oosthuyse et |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | cytochrome c oxidase | 1.0 | p experiments were performed on vulnerable hypoglossal motoneurones mns and mitochondrial function was disturbed by bath application of 1_amp_#x02013;2 m m sodium cyanide cn which inhibits complex iv cytochrome c oxidase of the electron transport chain. |
| 31395 | COX8B | cytochrome c oxidase, subunit 8B pseudogene | cytochrome c oxidase | 1.0 | we investigated the impact of a disturbed respiratory chain on membrane currents and [ca 2+ ] i using cyanide cn a known inhibitor of cytochrome c oxidase complex iv . |
| 12680 | VEGFA | vascular endothelial growth factor A | vascular endothelial growth factor | 1.0 | this is based on the observation that impaired vascular endothelial growth factor vegf synthesis due to hypoxia selectively damages mns oosthuyse et al 2001 ; lambrechts et al 2003 . |