4.5 Article

Inhibition of brain mitochondrial respiration by dopamine and its metabolites: implications for Parkinson's disease and catecholamine-associated diseases

期刊

JOURNAL OF NEUROCHEMISTRY
卷 91, 期 4, 页码 788-795

出版社

WILEY
DOI: 10.1111/j.1471-4159.2004.02747.x

关键词

dopamine; catecholamines; mitochondria; neurodegeneration

资金

  1. NINDS NIH HHS [NS36157] Funding Source: Medline

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A structure - potency study examining the ability of dopamine (DA), its major metabolites and related amine and acetate congeners to inhibit NADH-linked mitochondrial O-2 consumption was carried out to elucidate mechanisms by which DA could induce mitochondrial dysfunction. In the amine studies, DA was the most potent inhibitor of respiration (IC50 7.0 mM) compared with 3-methoxytryramine (3-MT, IC50 19.6 mM), 3,4-dimethoxyphenylethylamine (IC50 28.6 mM), tyramine (IC50 40.3 mM) and phenylethylamine (IC50 58.7 mM). Addition of monoamine oxidase (MAO) inhibitors afforded nearly complete protection against inhibition by phenylethylamine, tyramine and 3,4-dimethoxyphenylethylamine, indicating that inhibition arose from MAO-mediated pathways. In contrast, the inhibitory effects of DA and 3-MT were only partially prevented by MAO blockade, suggesting that inhibition might also arise from two-electron catechol oxidation and quinone formation by DA and one-electron oxidation of the 4-hydroxyphenyl group of 3-MT. In the phenylacetate studies, 3,4-dihydroxyphenylacetic acid ( DOPAC) was equipotent with DA in inhibiting respiration (IC50 7.4 mM), further implicating the catechol reaction as the cause of inhibition. All other carboxylate congeners; phenylacetic acid (IC50 13.0 mM), 4-hydroxyphenylacetic acid (IC50 12.1 mM), 4-hydroxy-3-methoxyphenylacetic acid (HVA, IC50 12.0 mM) and 3,4-dimethoxyphenylacetic acid (IC50 10.2 mM), were equipotent respiratory inhibitors and two- to fourfold more potent than their corresponding amine. These latter findings suggest that the phenylacetate ion can also contribute independently to mitochondrial inhibition. In summary, mitochondrial respiration can be inhibited by DA and its metabolites by four distinct MAO-dependent and independent mechanisms.

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