Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic complex I inhibition caused by rotenone induces features of Parkinson's disease in rats, including selective nigrostriatal dopaminergic degeneration and Lewy bodies with alpha-synuclein-positive inclusions. To determine the mechanisms underlying rotenone-induced neuronal death, we used an in vitro model of human dopaminergic SH-SY5Y cells. In rotenone-induced cell death, rotenone induced Bad dephosphorylation without changing the amount of Bad proteins. Rotenone also increased the amount of alpha-synuclein in cells showing morphological changes in response to rotenone. Because Bad and alpha-synuclein are known to bind to 14-3-3 proteins, we examined the effects of rotenone on these complexes. Whereas a decreased Bad amount bound to 14-3-3 proteins, rotenone increased alpha-synuclein binding to these proteins. Because dephosphorylation by calcineurin activates Bad, we examined the possible involvement of Bad activation in rotenone-induced apoptosis by using the calcineurin inhibitor tacrolimus (FK506). Tacrolimus suppressed two rotenone-induced actions: Bad dephosphorylation and apoptosis. Furthermore, the inhibition of caspase-9, which functions downstream from Bad, completely suppressed rotenone-induced apoptosis. Our findings demonstrate that Bad activation plays a role in rotenone-induced apoptosis of SH-SY5Y cells.
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PMID:Rotenone induces apoptosis via activation of bad in human dopaminergic SH-SY5Y cells. 1528 Apr 38

PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential.
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PMID:Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. 1949 85

In higher plants, the chloroplast NAD(P)H dehydrogenase (NDH) complex mediates photosystem I (PSI) cyclic and chlororespiratory electron transport. We reported previously that NDH interacts with the PSI complex to form a supercomplex (NDH-PSI). In this study, NDH18 and FKBP16-2 (FK506 Binding Protein 16-2), detected in the NDH-PSI supercomplex by mass spectrometry, were shown to be NDH subunits by the analysis of their knockdown lines. On the basis of extensive mutant characterization, we propose a structural model for chloroplast NDH, whereby NDH is divided into four subcomplexes. The subcomplex A and membrane subcomplex are conserved in cyanobacteria, but the subcomplex B and lumen subcomplex are specific to chloroplasts. Two minor light-harvesting complex I proteins, Lhca5 and Lhca6, were required for the full-size NDH-PSI supercomplex formation. Similar to crr pgr5 double mutants that completely lack cyclic electron flow activity around PSI, the lhca6 pgr5 double mutant exhibited a severe defect in growth. Consistent with the impaired NDH activity, photosynthesis was also severely affected in mature leaves of lhca6 pgr5. We conclude that chloroplast NDH became equipped with the novel subcomplexes and became associated with PSI during the evolution of land plants, and this process may have facilitated the efficient operation of NDH.
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PMID:Efficient operation of NAD(P)H dehydrogenase requires supercomplex formation with photosystem I via minor LHCI in Arabidopsis. 1990 70

The development of a diagnostic technology that can accurately determine the pathological progression of ischemic stroke and evaluate the therapeutic effects of cerebroprotective agents has been desired. We previously developed a novel PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-(18)F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([(18)F]BCPP-EF) for detecting activity of mitochondrial complex I (MC-I). This probe was shown to visualize neuronal damage in the living brain of rodent and primate models of neurodegenerative diseases. In the present study, [(18)F]BCPP-EF was applied to evaluate the therapeutic effects of a neuroprotectant, liposomal FK506 (FK506-liposomes), on cerebral ischemia/reperfusion (I/R) injury in transient middle cerebral artery occlusion rats. The PET imaging using [(18)F]BCPP-EF showed a prominent reduction in the MC-I activity in the ischemic brain hemisphere. Treatment with FK506-liposomes remarkably increased the uptake of [(18)F]BCPP-EF in the ischemic side corresponding to the improvement of blood flow disorders and motor function deficits throughout the 7 days after I/R. Additionally, the PET scan could diagnose the extent of the brain damage accurately and showed the neuroprotective effect of FK506-liposomes at Day 7, at which 2, 3, 5-triphenyltetrazolium chloride staining couldn't visualize them. Our study demonstrated that the PET technology using [(18)F]BCPP-EF has a potent capacity to evaluate the therapeutic effect of drug candidates in living brain.
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PMID:Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-I activity. 2744 54