Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methyl-4-phenylpyridinium ion (MPP(+)), a specific dopaminergic neurotoxin, inhibits mitochondrial complex I activity, generates reactive oxygen species (ROS), reduces ATP production, and induces cell death. We explored changes in expression of uncoupling proteins (UCPs 2, 4, and 5) following MPP(+)-induced toxicity in SK-N-SH cells over 72 hr at the transcriptional (quantification of mRNA by real-time RT-PCR) and translational (Western analysis) levels. UCP5 mRNA and protein were markedly up-regulated (1 mM MPP(+) at 72 hr caused a twofold increase, P < 0.01), as was UCP4 mRNA, albeit to a much lesser extent. Surprisingly, UCP2 mRNA levels decreased at 24 hr (P < 0.05) but thereafter significantly increased to greater than control levels at 72 hr (P < 0.05), although UCP2 protein levels were decreased throughout (1 mM MPP(+) at 72 hr caused a reduction of 50%, P < 0.01). The increase in ROS production may be attenuated by UCP4 and UCP5 up-regulation. The consequence of decreased UCP2 levels is unclear, although this may represent an adaptive response to declines in ATP levels, the subsequent increase in mRNA being a response to further increases in oxidative stress.
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PMID:Methyl-4-phenylpyridinium ion modulates expression of mitochondrial uncoupling proteins 2, 4, and 5 in catecholaminergic (SK-N-SH) cells. 1594 57

Mitochondrial uncoupling proteins (UCPs) uncouple oxidative phosphorylation from ATP synthesis. We explored the neuroprotective role of UCP4 with its stable overexpression in SH-SY5Y cells, after exposure to either MPP(+) or dopamine to induce ATP deficiency and oxidative stress. Cells overexpressing UCP4 proliferated faster in normal cultures and after exposure to MPP(+) and dopamine. Differentiated UCP4-overexpressing cells survived better when exposed to MPP(+) with decreased LDH release. Contrary to the mild uncoupling hypothesis, UCP4 overexpression resulted in increased absolute ATP levels (with ADP/ATP ratios similar to those of controls under normal conditions and ADP supplementation) associated with increased respiration rate. Under MPP(+) toxicity, UCP4 overexpression preserved ATP levels and mitochondrial membrane potential (MMP) and reduced oxidative stress; the preserved ATP level was not due to increased glycolysis. Under MPP(+) toxicity, the induction of UCP2 expression in vector controls was absent in UCP4-overexpressing cells, suggesting that UCP4 may compensate for UCP2 expression. UCP4 function does not seem to adhere to the mild uncoupling hypothesis in its neuroprotective mechanisms under oxidative stress and ATP deficiency. UCP4 overexpression increases cell survival by inducing oxidative phosphorylation, preserving ATP synthesis and MMP, and reducing oxidative stress.
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PMID:Mitochondrial UCP4 attenuates MPP+ - and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression. 1915 Apr

We explored the protective mechanisms of human neuronal mitochondrial uncoupling protein-5 (UCP5) in MPP(+)- and dopamine-induced toxicity after its stable overexpression in SH-SY5Y cells. We raised specific polyclonal antibodies. Overexpressed UCP5 localized in mitochondria but not in cytosol. UCP5 overexpression increased proton leak, decreased mitochondrial membrane potential (MMP), reduced ATP production, and increased overall oxygen consumption (demonstrating uncoupling activity). UCP5 overexpression did not affect other neuronal UCP expression (UCP2 and UCP4). Overexpressing UCP5 is protective against MPP(+)- and dopamine-induced toxicity. MPP(+) and dopamine exposure for 6h reduced MMP and increased superoxide levels. ATP levels in UCP5-overexpressing cells were preserved under MPP(+) and dopamine toxicity, comparable to levels in untreated vector controls. At 24h, UCP5 overexpression preserved MMP, ATP levels, and cell survival; attenuated superoxide generation; and maintained oxidative phosphorylation as indicated by lower lactate levels. MPP(+) and dopamine exposure induced UCP5 mRNA transcription but did not decrease transcript degradation, as inhibition of transcription by actinomycin-D abolished induction by either toxin. Compared with our previous studies on UCP4, we observed functional differences between UCP4 and UCP5 in enhancing mitochondrial efficiency. These neuronal UCP homologues may work synergistically to maintain oxidative balance (through uncoupling activities) and ATP production (by modifying MMP).
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PMID:Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. 2060 Aug 37

Astrocytes play crucial roles in determining the susceptibility to oxidative stress in the brain, and uncoupling protein 2 (UCP2) has been demonstrated to regulate reactive oxygen species (ROS) production. However, it is unclear whether UCP2 is expressed in astrocytes, and whether it participates in the regulation of astrocytic functions. Here we show that UCP2 knockout exacerbated dopaminergic neuron loss in a murine model of 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD), accompanied by overactivation of astrocytes. We further detected expression of UCP2 in primary cultures of mesencephalic astrocytes. UCP2 knockout increased intracellular ROS production and induced oxidative stress in response to l-methyl-4-phenylpyridinium (MPP(+)) treatment. Subsequently, UCP2 deficiency exacerbated endoplasmic reticulum (ER) stress, as evidenced by the upregulations of C/EBP homologous protein (CHOP), cleavage of caspase-12, and aggravated neuroinflammation via the activation of nod-like receptor protein 3 (NLRP3) inflammasomes in astrocytes. Collectively, our study indicates that UCP2 expressed in astrocytes modulates ER stress and neuroinflammation, and is crucial for the survival of dopaminergic neuron in the pathogenesis of PD. These findings gives us insights into the potential of UCP2 as a novel therapeutic avenue for PD treatment.
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PMID:Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. 2404 71