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The dopamine metabolite aminochrome inhibits mitochondrial complex I and modifies the expression of iron transporters DMT1 and FPN1

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Abstract

Hallmarks of idiopathic and some forms of familial Parkinson’s disease are mitochondrial dysfunction, iron accumulation and oxidative stress in dopaminergic neurons of the substantia nigra. There seems to be a causal link between these three conditions, since mitochondrial dysfunction can give rise to increased electron leak and reactive oxygen species production. In turn, recent evidence indicates that diminished activity of mitochondrial complex I results in decreased Fe–S cluster synthesis and anomalous activation of Iron Regulatory Protein 1. Thus, mitochondrial dysfunction could be a founding event in the process that leads to neuronal death. Here, we present evidence showing that at low micromolar concentrations, the dopamine metabolite aminochrome inhibits complex I and ATP production in SH-SY5Y neuroblastoma cells differentiated into a dopaminergic phenotype. This effect is apparently direct, since it is replicated in isolated mitochondria. Additionally, overnight treatment with aminochrome increased the expression of the iron import transporter divalent metal transporter 1 and decreased the expression of the iron export transporter ferroportin 1. In accordance with these findings, cells treated with aminochrome presented increased iron uptake. These results suggest that aminochrome is an endogenous toxin that inhibits by oxidative modifications mitochondrial complex I and modifies the levels of iron transporters in a way that leads to iron accumulation.

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Acknowledgments

This work was financed by project ICM-P05-001-F from the Millennium Scientific Initiative, Ministerio de Economía, Chile, and Fondecyt 1100165 (JS-A).

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Authors and Affiliations

  1. Department of Biology, Faculty of Sciences, Universidad de Chile and Cell Dynamics and Biotechnology Institute, Santiago, Chile

    Pabla Aguirre, Pamela Urrutia, Victoria Tapia & Marco T. Núñez

  2. Department of Molecular and Clinical Pharmacology, Faculty of Medicine, Universidad de Chile, Av. Independencia 1027, Santiago, Chile

    Monica Villa, Irmgad Paris & Juan Segura-Aguilar

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  1. Pabla Aguirre
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  2. Pamela Urrutia
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  3. Victoria Tapia
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  4. Monica Villa
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  7. Marco T. Núñez
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Correspondence to Marco T. Núñez.

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Supplemental Figure 1

Cell viability determined by LDH leakage assay. Differentiated SH-SY5Y cells were exposed to different concentrations of aminochrome for 20 h. LDH leakage was calculated as the percentage of LDH in the medium versus total LDH activity in the cells. The results are shown normalized to control. Mean ± SEM of three separate experiments. * P< 0.05, ** P< 0.01 compared to control (TIFF 1260 kb)

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Aguirre, P., Urrutia, P., Tapia, V. et al. The dopamine metabolite aminochrome inhibits mitochondrial complex I and modifies the expression of iron transporters DMT1 and FPN1. Biometals 25, 795–803 (2012). https://doi.org/10.1007/s10534-012-9525-y

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  • DOI: https://doi.org/10.1007/s10534-012-9525-y

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