MANGANESE INHIBITS MITOCHONDRIAL ACONITASE - A MECHANISM OF MANGANESENEUROTOXICITY

The symptoms of Mn-induced neurotoxicity resemble those of Parkinson's diseases. Since iron (Fe) appears to play a pivotal role in pathophys iology 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. Mitochondrial fractions prepared from rat brai n were preincubated with MnCl2 in vitro, followed by the enzyme assay. Mn treatment significantly inhibited mitochondrial aconitase activity (24% inhibition at 625 mu M to 81% at 2.5 mM, p < 0.05). The inhibito ry effect was reversible and Mn-concentration dependent, and was rever sed by the addition of Fe (0.05-1 mM) to the reaction mixture. In an i n vivo chronic Mn exposure model, rats received intraperitoneal inject ion of 6 mg/kg Mn as MnCl2 once daily for 30 consecutive days. Mn expo sure led to a region-specific alteration in total aconitase (i.e., mit ochondrial + cytoplasmic): 48.5% reduction of the enzyme activity in f rontal cortex (p < 0.01), 33.7% in striatum (p < 0.0963), and 20.6% in substantia nigra (p < 0.139). Chronic Mn exposure increased Mn concen trations in serum, CSF, and brain tissues. The elevation of Mn in all selected brain regions (range between 3.1 and 3.9 fold) was similar in magnitude to that in CSF (3.1 fold) rather than serum (6.1 fold). The present results suggest that Mn alters brain aconitase activity, whic h may lead to the disruption of mitochondrial energy production and ce llular Fe metabolism in the brain. (C) 1998 Elsevier Science B.V. All rights reserved.