Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,3-Dinitrobenzene (DNB) produces edematous, glio-vascular lesions in brainstem nuclei with high energy demands. Astrocytes in vulnerable brainstem nuclei appear to be an early and selective target of DNB and other nitroaromatic compounds, though the molecular basis of this susceptibility is poorly understood. It has been postulated that mitochondria are a principal target of DNB in sensitive cell types [Neuropathol. Appl. Neurobiol. 13 (5) (1987) 371], where redox-cycling of DNB increases levels of reactive oxygen species and disrupts cellular energy metabolism. The present study investigates the role of regional differences in activation of the mitochondrial permeability transition pore (mtPTP) by DNB in brainstem and cortical astrocytes and examines the expression of Bcl-2 proteins as potential regulators of mtPTP function. Neonatal rat astrocytes were cultured from both DNB-sensitive (brainstem) and insensitive (cortex) brain regions and evaluated for DNB-induced alterations in cell morphology and mitochondrial function. Exposure to DNB resulted in rapid changes in the morphology of brainstem astrocytes consistent with loss of ion homeostasis and initiation of necrotic cell death. These changes were not observed in cortical astrocytes at corresponding concentrations of DNB and were prevented in brainstem astrocytes by the mtPTP inhibitor, bongkrekic acid, suggesting that mitochondrial dysfunction is involved in DNB-induced morphological changes in brainstem astrocytes. Mitochondrial depolarization in brainstem astrocytes was observed at DNB concentrations as low as 10 microM, whereas no loss of mitochondrial membrane potential (DeltaPsi(mt)) occurred in cortical astrocytes at less than 100 microM DNB. DNB-induced loss of DeltaPsi(mt) followed apparent first-order kinetics, with EC(50)-values for half-maximal rates of mitochondrial depolarization of approximately 23 and approximately 290 microM in brainstem cortical astrocytes, respectively. DNB-induced mitochondrial depolarization was prevented by pretreatment with bongkrekic acid, indicating that loss of DeltaPsi(mt) was mediated by activation of the mtPTP. Inhibition of succinate dehydrogenase (SDH) activity occurred in astrocytes from both brain regions exposed to DNB and was blocked in brainstem, but not cortical, astrocytes by bongkrekic acid. Constitutive expression of Bcl-X(L) was high in cortical tissue and astrocytes, whereas Bax expression was low. However, Bax was highly expressed in brainstem tissue and astrocytes and Bcl-X(L) expression was markedly lower. The expression of Bcl-2 was similar in both brain regions. These data suggest that the selective vulnerability of brainstem astrocytes to DNB is due to a lower threshold for activation of the mtPTP that is be mediated, in part, by distinct expression patterns of Bcl-2 proteins rather than by intrinsic differences in susceptibility of the electron transport chain.
 ...
PMID:Regional variation in the activation threshold for 1,3-DNB-induced mitochondrial permeability transition in brainstem and cortical astrocytes. 1278 4

1,3-Dinitrobenzene (DNB) produces edematous, glio-vascular lesions that are initially confined to brainstem nuclei with high energy requirements in rats and mice. Perturbation of energy producing processes in the cell is known to induce formation of the mitochondrial permeability transition pore (mtPTP) complex. Selective vulnerability of brainstem astrocytes to DNB is mediated by a 10-fold lower threshold for opening of the cyclosporin A-inhibitable mitochondrial permeability transition (MPT) pore than their cortical counterparts. Other nitrocompounds, such as 3-nitropropionic acid, selectively interfere with regional energy metabolism, including mitochondrial succinate dehydrogenase activity. However, the link between DNB-induced onset of the MPT and disruption of energy producing processes in the astrocyte remains unclear. The effects of DNB on succinate dehydrogenase activity were evaluated in cultured neonatal rat and mouse brainstem and cortical astrocytes. Both histochemical and spectrophotometric assays confirmed significant temporal inhibition of SDH activity in brainstem and cortical astrocytes 0.5, 2 and 5h following exposure to 100 microM DNB in vitro. Although DNB-induced inhibition of SDH was significantly decreased by CsA pretreatment in brainstem astrocytes after 0.5 and 2h and with a second pore inhibitor, bongkrekic acid (BKA) after 5h, both inhibitors failed to reduce inhibition of SDH activity in cortical astrocytes. These data suggest that DNB-induced inhibition of SDH may be independent of differential regional activation of the mtPTP complex in astrocytes and that an unidentified cyclosporin A-inhibitable factor mediates DNB-induced loss of SDH function.
 ...
PMID:1,3-Dinitrobenzene inhibits mitochondrial complex II in rat and mouse brainstem and cortical astrocytes. 1278 5