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Copper depletion increases the mitochondrial-associated SOD1 in neuronal cells

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Abstract

The role of copper in the toxicity of mutant copper-dependent enzyme superoxide dismutase (SOD1) found in patients affected with the familial form of amyotrophic lateral sclerosis (fALS) is widely debated. Here we report that treatment of human neuroblastoma cells SH-SY5Y with a specific copper chelator, triethylene tetramine (Trien) induces the decrease of intracellular copper level, paralleled by decreased activity of SOD1. A comparable effect is observed in mouse NSC-34-derived cells, a motoneuronal model, transfected for the inducible expression of either wild-type or G93A mutant human SOD1, one of the mutations associated with fALS. In both cell types, the drop of SOD1 activity is not paralleled by the same extent of decrease in SOD1 protein content. This discrepancy can be explained by the occurrence of a fraction of copper-free SOD1 upon copper depletion, which is demonstrated by the partial recovery of the enzyme activity after the addition of copper sulphate to homogenates of SH-SY5Y cells. Furthermore, copper depletion produces the enrichment of the physiological mitochondrial fraction of SOD1 protein, in both cells models. However, increasing the fraction of mitochondrial, possibly copper-free, mutant human SOD1 does not further alter mitochondrial morphology in NSC-34-derived cells. Thus, copper deficiency is not a factor which may worsen mitochondrial damage, which is one of the earliest events in fALS associated with mutant SOD1.

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Acknowledgments

This study was partially supported by a MIUR grant (PRIN 2008J2LRWZ) to L. R. and A. F.

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Author notes

  1. Mario Arciello

    Present address: Laboratory of Molecular Virology, Andrea Cesalpino Foundation, Via Sicilia 169, 00187, Rome, Italy

  2. Sara D’Annibale

    Present address: Hubrecht Institute-KNAW, University Medical Center Utrecht, Uppsalaan 8, 3584 CT, Utrecht, The Netherlands

Authors and Affiliations

  1. Department of Biology, “Tor Vergata” University of Rome, Via della Ricerca Scientifica 1, 00133, Rome, Italy

    Mario Arciello, Concetta Rosa Capo, Sara D’Annibale, Maria Teresa Carrì & Luisa Rossi

  2. Laboratory of Neurochemistry, Fondazione Santa Lucia, IRCCS, Rome, Italy

    Mauro Cozzolino, Alberto Ferri & Maria Teresa Carrì

  3. Department of Psychobiology and Psychopharmacology, Institute of Neuroscience, CNR, Rome, Italy

    Alberto Ferri

  4. Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Rome, Italy

    Luisa Rossi

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  1. Mario Arciello
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  2. Concetta Rosa Capo
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  3. Sara D’Annibale
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  4. Mauro Cozzolino
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  6. Maria Teresa Carrì
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  7. Luisa Rossi
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Correspondence to Luisa Rossi.

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Arciello, M., Capo, C.R., D’Annibale, S. et al. Copper depletion increases the mitochondrial-associated SOD1 in neuronal cells. Biometals 24, 269–278 (2011). https://doi.org/10.1007/s10534-010-9392-3

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  • DOI: https://doi.org/10.1007/s10534-010-9392-3

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