Paradoxical effects of copper and manganese on brain mitochondrial function

Defects in the mitochondrial genome have been associated with Parkinson's a nd Alzheimer's disease, and apoptosis can be triggered by the presence of e nergetically compromised mitochondria. Thus, in this study we have examined whether the divalent cations CU2+ and Mn2+ could influence mitochondrial f unction ia vitro. Mitochondrial electron transport was dose and time depend ently reduced by CU2+ to a greater extent with succinate as a substrate. Fo llowing a 60min preincubation period, Mn2+ dose dependently inhibited elect ron transport to a greater extent with lactate and malate. In contrast, par adoxical effects were seen following a 5min preincubation period with Mn2+. CU2+ dose-dependently reduced NADH-dependent lactate dehydrogenase (LDH) a ctivity, with almost complete inhibition apparent at 10 muM. An initial ind uction of LDH by 10 muM Mn2+ was partially reversed by higher concentration s of the metal. CU2+ dose-dependently reduced flavin adenine dinucleotide ( FAD)dependent monoamine oxidase A (MAO-A) activity in a time-independent ma nner, with an IC50 value approximate to 20 muM, whereas Mn2+ had no effect. In conclusion, it is proposed that CU2+ and Mn2+ have differential effects on nicotinamide adenine dinucleotide (NAD) and FAD-dependent mitochondrial enzymes at the level of the essential cofactors. CU2+ appears to exert an inhibitory effect on both NAD and FAD-dependent enzymes, but predominantly against the latter, including MAO-A and succinate dehydrogenase. The comple x responses to Mn2+ may be due to dose-related effects on the interconversi on of NAD and NADH and reversible enzymatic reactions employing this nucleo tide cofactor. (C) 2001 Elsevier Science Inc. All rights reserved.