Disease relevance of Aco2

• RESULTS: In the present study we show that iron overload in lipopolysaccharide-treated C. parvum-primed hepatocytes downregulated the RNA binding of iron regulatory protein-1 and aconitase activity [1].
• Since iron (Fe) appears to play a pivotal role in pathophysiology of Parkinson's disease, we set out to test the hypothesis that alterations in Fe-requiring enzymes such as aconitase contribute to Mn-induced neurotoxicity [2].
• Recent studies suggest that manganese-induced neurodegenerative toxicity may be partly due to its action on aconitase, which participates in cellular iron regulation and mitochondrial energy production [3].
• Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia [4].

High impact information on Aco2

• Treatment of rat cortical cultures with NMDA, KA, or the intracellular O2- generator PQ2+ produced a selective and reversible inactivation of aconitase, which closely correlated with subsequent cell death produced by these agents [5].
• The SOD mimetic, but not its less active congener, attenuated both aconitase inactivation and cell death produced by NMDA, KA, and PQ2+ [5].
• Treatment with cyclosporine blocked the (i) elevation of plasma nitrate + nitrite, (ii) up-regulation of iNOS protein, (iii) decrease in Fe-S cluster EPR signal, (iv) formation of dinitrosyl-iron complexes, and (v) loss of aconitase enzyme activity [6].
• Increased levels of reactive oxygen species and mitochondrial 3-nitrotyrosine and 4-hydroxynonenal protein adducts and decreased mitochondrial aconitase activity and mitochondrial membrane potential were observed in mE10 and mE27 cells treated with BSO [7].
• Here we provide evidence for the first mechanism and show that superoxide activates UCP2 in rat kidney mitochondria from the matrix side of the mitochondrial inner membrane: (i) Exogenous superoxide inhibited matrix aconitase, showing that external superoxide entered the matrix [8].

Biological context of Aco2

• The O(2)(-)* leaked from the electron transport chain, oxidatively damages the mitochondrial aconitase, releasing a free Fe(2+) [9].
• Assessment of electron transport chain complexes and Krebs cycle enzymes revealed that alpha-ketoglutarate dehydrogenase (KGDH), succinate dehydrogenase (SDH), and aconitase were susceptible to H(2)O(2) inactivation [10].
• Moreover, a significant decrease of mitochondrial aconitase, leading to a rise of hydroperoxides, and islet beta-cell apoptosis, involving caspase-3 and -8, is observed [11].
• Thus, depending on the pro-oxidant species, the level and duration of the oxidative stress, and the metabolic state of the mitochondria, aconitase may undergo reversible modulation in activity or progress to [4Fe-4S](2+) cluster disassembly and proteolytic degradation [12].
• These observations suggest that some form of posttranslational modification of aconitase other than release of iron is responsible for enzyme inactivation [12].

Anatomical context of Aco2

• Reversible inactivation of superoxide-sensitive aconitase in Abeta1-42-treated neuronal cell lines [13].
• Aconitase activity in prostate mitochondria was approximately 10% of the activity observed in kidney preparations [14].
• The aconitase activity of cytosol and mitochondria increased upon exposure to air for 7 1/2 hr [15].
• Aconitase activity in small intestine homogenate was also increased by clofibrate [16].
• Prostate epithelial cells possess a uniquely limiting mitochondrial (m-) aconitase activity that minimizes their ability to oxidize citrate [17].

Associations of Aco2 with chemical compounds

• However, in heat-shocked cells, because of higher MnSOD activity, the excess H(2)O(2) causes irreversible damage to the mitochondrial aconitase enzyme, thus inhibiting its activity [9].
• Heat shock-induced attenuation of hydroxyl radical generation and mitochondrial aconitase activity in cardiac H9c2 cells [9].
• The aconitase-released Fe(2+) combines with H(2)O(2) to generate *OH via a Fenton reaction and the oxidized Fe(3+) recombines with the inactivated enzyme after being reduced to Fe(2+) by other cellular reductants, turning it over to be active [9].
• We found that aconitase can undergo reversible citrate-dependent modulation in activity in response to pro-oxidants [18].
• Aconitase was reactivated upon incubation of cellular extracts with iron and sulfur, suggesting that Abeta causes the release of iron from 4Fe-4S clusters [13].

Regulatory relationships of Aco2

• Both Meth-arg and N alpha-p-tosyl-L-lysine chloromethyl ketone (0.1 mM), a protease inhibitor, could completely counteract the IL-1 beta-induced increases in nitrite production and inhibition of aconitase activity and glucose oxidation rates [19].

Other interactions of Aco2

• High-fat diet upregulated the forkhead transcription factor Foxo3a, and suppressed mitochondrial aconitase activity without affecting expression of the caloric sensitive gene silent information regulator 2 (Sir2), protein nitrotyrosine formation, lipid peroxidation and apoptosis [20].
• Thus, islets were isolated from adult rats, precultured for 3-5 days in medium RPMI-1640 plus 10% fetal calf serum, and then exposed to IL-1 beta for different time periods, after which islet nitrite production and aconitase activity were determined [19].
• Aconitase activity decreased in these regions of the kidney following leptin administration by 44.8% and 45.1%, respectively [21].
• In cultured VSMCs, phenylephrine caused time- and dose-dependent ROS generation (aconitase activity), had similar efficacy to thrombin (1 U/mL), and was eliminated by the superoxide dismutase (SOD) mimetic Mn-(III)-tetrakis-(4-benzoic-acid)-porphyrin-chloride (200 micromol/L) and Tiron [22].

Analytical, diagnostic and therapeutic context of Aco2

• Moreover, Western blotting of the mitochondrial fraction revealed that most of the mitochondrial aconitase in HD caudate is present as high-Mr aggregates [23].
• We examined iron nitrosylation of non-heme protein and enzymatic activity of the Fe-S cluster protein, aconitase, in acute cardiac allograft rejection [6].
• Aconitase enzyme activity was decreased to approximately 50% of that observed in isograft controls by POD4 [6].
• Protein components unambiguously identified by peptide mapping are citrate synthase, aconitase, and pyruvate carboxylase [24].
• Recovery of left ventricular (LV) contractile function and aconitase activity during reperfusion were inversely related to the burst of radical production and were significantly higher in hearts initially reperfused with 95% O2 (P < 0.001) [25].

References