Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.
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PMID:Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat. 898 27

Glutathione deficiency is commonly associated with mitochondrial complex I dysfunction and loss of viability in neurones, but not in glia. In order to address the possible mechanism responsible for this cellular difference, the regulation of mitochondrial complex I expression by glutathione depletion was investigated in glial cells. Incubation of rat-cultured astrocytes and C6 glioma cells with the specific gamma-glutamylcysteine synthetase inhibitor L-buthionine-(S:,R:)-sulfoximine (L-BSO; 0.1-1 mM) decreased the total specific content of glutathione in a dose- and time-dependent fashion. Northern blot analyses revealed that glutathione deficiency caused by L-BSO (0.1 mM) was associated with a twofold enhancement in complex I regulatory subunit ND6 (mitochondrially encoded) mRNA expression after 24-72 h. This effect was accompanied by a twofold increase in complex-I activity at 72 h in L-BSO-treated cells, as compared with control cells, but complex II-III, complex IV and citrate synthase activities were unaltered. It is suggested that the oxidative stress caused by glutathione depletion in glial cells would up-regulate complex-I activity by enhancing the expression of the mitochondrially encoded regulatory subunit. These results could offer further insight into the different degree of cellular susceptibility observed in glial vs. neuronal cells against oxidative stress.
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PMID:Depletion of glutathione up-regulates mitochondrial complex I expression in glial cells. 1123 44