)| PMID |
16624679 ( ) |
|---|---|
| Title | Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis. |
| Abstract | G93A Cu/Zn superoxide dismutase (SOD1), a human mutant SOD1 associated with familial amyotrophic lateral sclerosis, increased the toxicity of the mitochondrial toxin rotenone in the NSC-34 motoneuronal cell line. G93ASOD1 cells died more than untransfected and wild-type SOD1 cells after 6 and 24h exposure to 12.5 microM rotenone. Biparametric flow cytometry showed that rotenone induced rapid hyperpolarization of mitochondrial membrane potential (deltapsi(m)) in all the cell lines, followed by depolarization, and then by cell death. However, G93ASOD1 mitochondria were significantly more likely to shift from a hyperpolarized to a depolarized condition, and within the still viable cell population there was a higher proportion with depolarized mitochondria, a condition that can be envisaged as a commitment to cell death. ATP, which is needed to prevent loss of deltapsi(m), decreased more rapidly and to a greater extent in rotenone-treated G93ASOD1 cells than in the untransfected and wtSOD1cells. In all the cell lines, 1h after rotenone exposure, mitochondrial hyperpolarization was accompanied by the formation of a comparable amount of reactive oxygen species. However, G93ASOD1 cells reached the highest reactive oxygen species level since their basal level was higher than in untransfected and wild-type SOD1 cells. Our findings indicate that the mutant protein G93ASOD1 enhances the vulnerability of motor neurons to rotenone by mechanism(s) involving oxidative stress and perturbed mitochondrial homeostasis. This suggests that motor neurons from individuals carrying the mutant G93ASOD1 are at greater risk of death after inhibition of the electron transport chain. Mario Negri, Via Eritrea 62, 20157 Milan, Italy. |
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)) | 33 | SOD1 | hSOD1 | mSOD1 | |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | 5 | Bcl-2 | Bcl-2-like | bcl 2 | |
| 9257 | PPID | peptidylprolyl isomerase D (cyclophilin D) | 3 | cyclophilin d | Cyp-D | cyp d | |
| 10990 | SLC25A4 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 | 3 | ANT | |
| 16554 | SLC25A6P1 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6, pseudogene 1 | 2 | adenine nucleotide translocator | |
| 1158 | TSPO | translocator protein (18kDa) | 2 | peripheral benzodiazepine receptor | PBR | |
| 12517 | UCP1 | uncoupling protein 1 (mitochondrial, proton carrier) | 1 | UCPs | |
| 1991 | CKB | creatine kinase, brain | 1 | creatine kinase | |
| 949 | BAK1 | BCL2-antagonist/killer 1 | 1 | Bak | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | G93A Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 a human mutant SOD1 associated with familial amyotrophic lateral sclerosis |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 a human mutant SOD1 associated with familial amyotrophic lateral sclerosis increased the toxicity of |
| 10990 | SLC25A4 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 | ANT | 0.0 | mitochondrial ETC the F0F1-ATPase and the adenine nucleotide translocator (ANT) ANT ( Fig 1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | have mutant forms of Cu/Zn Cu Zn superoxide dismutase (SOD1), SOD1 a free radical-scavenging enzyme that converts the superoxide anion radical |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | Apparently the motor neuron toxicity of mutant SOD1 is due to a _amp_#x201c gain of function(s)_amp_#x201d; function s |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | oxidative chemistry and/or and or misfolding and aggregation of mutant SOD1 11 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | The identification of SOD1 mutations as a cause of ALS has served for creating |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | experimental models of the disease expressing mutant forms of human SOD1 in laboratory animals and cells |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | conversion more in NSC-34 motoneuronal cells expressing mutant (G93A) G93A SOD1 than in those expressing wild-type (wt) wt SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | (G93A) G93A SOD1 than in those expressing wild-type (wt) wt SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | stably expressing wild-type (wt) wt or mutant (G93A) G93A human SOD1 were generated and checked for SOD1 expression as previously described |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | mutant (G93A) G93A human SOD1 were generated and checked for SOD1 expression as previously described 43 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | lines stably transfected with cDNAs of human wt/G93A wt G93A SOD1 were generated |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | Western blotting indicated similar levels of murine SOD1 protein in all the lines wt or the G93A mutant |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | lines wt or the G93A mutant form of the human SOD1 protein was expressed at comparable levels ( Fig 2 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | The greater susceptibility of cells transfected with G93A SOD1 to inhibition of complex I of the ETC persisted after |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | To see why the presence of G93A SOD1 increased the motor neuron cells_amp_#x2019 susceptibility to rotenone we considered |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | toxin for motor neurons of humans with mutant forms of SOD1 and for unraveling the toxicity of these mutant forms |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | in the toxic _amp_#x201c gain of function_amp_#x201d of mutant SOD1(s) SOD1 s 11 free radical scavengers were protective in several models |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | might affect the mitochondria is reinforced by the finding that SOD1 also localizes in the mitochondrial intermembrane space and matrix 39 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | space and matrix 39 48 and 51 and that mutant SOD1 forms aggregates in the matrix 51 |
| 10990 | SLC25A4 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 | ANT | 0.0 | For example ANT changes its conformation after oxidative stress and this promotes opening |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | Bcl-2 | 1.3 | Interestingly Bcl-2 which has protective activity against oxidative stress 24 and prevents |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | of mitochondrial membrane potential 45 and 49 was trapped by SOD1 aggregates in spinal cord mitochondria of transgenic SOD1 mice and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | trapped by SOD1 aggregates in spinal cord mitochondria of transgenic SOD1 mice and in spinal cord homogenates from human samples 40 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | factor for motor neurons of individuals carrying the mutant G93A SOD1 and might act in concert with other genetic defects associated |
| 10990 | SLC25A4 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 | ANT | 0.0 | released into the cytosol via the adenine nucleotide translocator (ANT) ANT and the _amp_#x201c voltage-dependent_amp_#x201d anion channel (VDAC), VDAC which are |
| 1158 | TSPO | translocator protein (18kDa) | PBR | 0.3 | components of this complex are the peripheral benzodiazepine receptor (PBR), PBR creatine kinase (CK), CK hexokinase II (HK), HK cyclophilin D |
| 9257 | PPID | peptidylprolyl isomerase D (cyclophilin D) | Cyp-D | 1.0 | kinase (CK), CK hexokinase II (HK), HK cyclophilin D (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | Bcl-2-like | 1.5 | II (HK), HK cyclophilin D (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 |
| 949 | BAK1 | BCL2-antagonist/killer 1 | Bak | 0.3 | D (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | Bcl-2 | 1.3 | (Cyp-D) Cyp-D and Bax/Bcl-2-like Bax Bcl-2-like proteins (Bax, Bax Bak Bcl-2 |
| 12517 | UCP1 | uncoupling protein 1 (mitochondrial, proton carrier) | UCPs | 0.3 | Uncoupling proteins (UCPs) UCPs provide an alternative route for H to re-enter the matrix |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | SOD1 is present in the cytosol and in the mitochondrial intermembrane |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | Fig 2._amp_#xa0 Expression of human SOD1 in the NSC-34 cellular model of FALS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | lane 2 human wild-type (lane lane 3 or G93A mutant SOD1 (lane lane 4 was done using a polyclonal anti-human SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | SOD1 (lane lane 4 was done using a polyclonal anti-human SOD1 antibody that crossreacts with murine SOD1(mSOD1) SOD1 mSOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | a polyclonal anti-human SOD1 antibody that crossreacts with murine SOD1(mSOD1) SOD1 mSOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | mSOD1 | 2.7 | polyclonal anti-human SOD1 antibody that crossreacts with murine SOD1(mSOD1) SOD1 mSOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | mSOD1 | 2.7 | The positions of mSOD1 and human SOD1(hSOD1) SOD1 hSOD1 are indicated in SDS-PAGE they |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 3.7 | The positions of mSOD1 and human SOD1(hSOD1) SOD1 hSOD1 are indicated in SDS-PAGE they can be resolved into |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | hSOD1 | 2.7 | The positions of mSOD1 and human SOD1(hSOD1) SOD1 hSOD1 are indicated in SDS-PAGE they can be resolved into two |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | mSOD1 | 2.7 | resolved into two bands due to the faster migration of mSOD1 |
| 16554 | SLC25A6P1 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6, pseudogene 1 | adenine nucleotide translocator | 1.0 | _#x201d; generating adenosine triphosphate atp through oxidative phosphorylation which relies on the activity of the four respiratory enzyme complexes of the mitochondrial etc the f0f1 atpase and the adenine nucleotide translocator ant fig 1 . |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl 2 | 1.0 | interestingly bcl 2 which has protective activity against oxidative stress [24] and prevents cell death induced by rotenone by blocking the loss of mitochondrial membrane potential [45] and [49] was trapped by sod1 aggr |
| 16554 | SLC25A6P1 | solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6, pseudogene 1 | adenine nucleotide translocator | 1.0 | atp is then released into the cytosol via the adenine nucleotide translocator ant and the _amp_#x201c;voltage dependent_amp_#x201d; anion channel vdac which are the core components of the mitochondrial membrane permeability pore. |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl 2 | 1.0 | other putative components of this complex are the peripheral benzodiazepine receptor pbr creatine kinase ck hexokinase ii hk cyclophilin d cyp d and bax/bcl 2 like proteins bax bak bcl 2 . |
| 9257 | PPID | peptidylprolyl isomerase D (cyclophilin D) | cyclophilin d | 1.0 | other putative components of this complex are the peripheral benzodiazepine receptor pbr creatine kinase ck hexokinase ii hk cyclophilin d cyp d and bax/bcl 2 like proteins bax bak bcl 2 . |
| 9257 | PPID | peptidylprolyl isomerase D (cyclophilin D) | cyp d | 1.0 | other putative components of this complex are the peripheral benzodiazepine receptor pbr creatine kinase ck hexokinase ii hk cyclophilin d cyp d and bax/bcl 2 like proteins bax bak bcl 2 . |
| 1991 | CKB | creatine kinase, brain | creatine kinase | 1.0 | other putative components of this complex are the peripheral benzodiazepine receptor pbr creatine kinase ck hexokinase ii hk cyclophilin d cyp d and bax/bcl 2 like proteins bax bak bcl 2 . |
| 1158 | TSPO | translocator protein (18kDa) | peripheral benzodiazepine receptor | 1.0 | other putative components of this complex are the peripheral benzodiazepine receptor pbr creatine kinase ck hexokinase ii hk cyclophilin d cyp d and bax/bcl 2 like proteins bax bak bcl 2 . |