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Calpain-mediated MPP+ toxicity in mitochondrial DNA depleted cells

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Abstract

MPP+ (1-methyl-4-phenylpyridium ion), a complex I — inhibiting metabolite of 1-methyl-4-phe-nyl-1,2,3,6-tetrahydropyridine (MPTP), causes anatomic-specific neurodegeneration. To evaluate the broader role of mitochondria in MPP+- induced cell death, we exposed neuron-like NT2 human teratocarcinoma cells with mtDNA(rho+) and without mtDNA (rho0) to MPP+. MPP+ minimized the ability of both rho+ and rho0 cells to reduce MTT. Only rho+ cells, though, initiated intrinsic pathway-mediated apoptosis. MPP+ also activated calpains in rho0 cell lines. The calpain inhibitor MDL 28710 was able to prevent the MPP+-related MTT reduction change in rho0 but not rho+ cells. We conclude that 1) MPP+-induced apoptosis requires functional mitochondria, 2) MPP+ activates calpains independent of respiratory chain inhibition, and 3) calpain activation mediates some aspects of MPP+ toxicity.

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Authors and Affiliations

  1. Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    A. Filipa Domingues, A. Raquel F. Esteves, Catarina R. Oliveira & Sandra M. Cardoso

  2. Department of Neurology, University of Virginia School of Medicine, 800394, Charlottesville, VA, USA

    Russell H. Swerdlow

  3. Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal

    Catarina R. Oliveira

  4. Institute of Biology, Faculty of Medicine, Univ. of Coimbra, 3004-504, Coimbra, Portugal

    Sandra M. Cardoso

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  1. A. Filipa Domingues
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  2. A. Raquel F. Esteves
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  3. Russell H. Swerdlow
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  4. Catarina R. Oliveira
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  5. Sandra M. Cardoso
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Correspondence to Sandra M. Cardoso.

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Domingues, A.F., Esteves, A.R.F., Swerdlow, R.H. et al. Calpain-mediated MPP+ toxicity in mitochondrial DNA depleted cells. neurotox res 13, 31–38 (2008). https://doi.org/10.1007/BF03033365

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  • DOI: https://doi.org/10.1007/BF03033365

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