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Lithium reduces the effects of rotenone-induced complex I dysfunction on DNA methylation and hydroxymethylation in rat cortical primary neurons

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Abstract

Rationale

Mitochondrial complex I dysfunction and alterations in DNA methylation levels are consistently reported in bipolar disorder (BD) and are regulated by lithium. One of the mechanisms by which lithium may exert its effects in BD is by improving mitochondrial complex I function. Therefore, we examined whether complex I dysfunction induces methylation and hydroxymethylation of DNA and whether lithium alters these effects in rat primary cortical neurons.

Methods

Rotenone was used to induce mitochondrial complex I dysfunction. Cell viability was measured by MTT assay, and ATP levels were assessed by Cell-Titer-Glo®. Complex I activity was measured using an ELISA-based assay. Apoptosis, DNA methylation, and hydroxymethylation levels were measured by immunocytochemistry.

Results

Rotenone decreased complex I activity and ATP production, but increased cell death and apoptosis. Rotenone treatment increased levels of 5-methylcytosine (5mc) and hydroxymethylcytosine (5hmc), suggesting a possible association between complex I dysfunction and DNA alterations. Lithium prevented rotenone-induced changes in mitochondrial complex I function, cell death and changes to DNA methylation and hydroxymethylation.

Conclusions

These findings suggest that decreased mitochondrial complex I activity may increase DNA methylation and hydroxymethylation in rat primary cortical neurons and that lithium may prevent these effects.

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Acknowledgment

The authors have no conflict of interest to disclose. The authors thank Brain & Behavior Research Foundation (Formerly NARSAD, ACA), CNPq/Brazil (GS), and Canadian Institutes of Health Research (CIHR) as sources of funding in support of this report (LTY and ACA).

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Authors and Affiliations

  1. Department of Psychiatry, University of Toronto, Medical Science Building, Room 4204, 1 king’s College Circle, Toronto, ON, M5S 1A8, Canada

    Gustavo Scola, L. Trevor Young & Ana C. Andreazza

  2. Department of Pharmacology, University of Toronto, Toronto, ON, Canada

    Helena K. Kim, L. Trevor Young & Ana C. Andreazza

  3. Centre for Addiction and Mental Health, Toronto, ON, Canada

    Gustavo Scola, Helena K. Kim, L. Trevor Young & Ana C. Andreazza

  4. Institute of Biotechnology, University of Caxias do Sul, Caxias do Sul, RS, Brazil

    Gustavo Scola & Mirian Salvador

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  1. Gustavo Scola
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  2. Helena K. Kim
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  3. L. Trevor Young
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  4. Mirian Salvador
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  5. Ana C. Andreazza
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Corresponding author

Correspondence to Ana C. Andreazza.

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Gustavo Scola and Helena K. Kim contribute equally for this study.

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Scola, G., Kim, H.K., Young, L.T. et al. Lithium reduces the effects of rotenone-induced complex I dysfunction on DNA methylation and hydroxymethylation in rat cortical primary neurons. Psychopharmacology 231, 4189–4198 (2014). https://doi.org/10.1007/s00213-014-3565-7

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  • DOI: https://doi.org/10.1007/s00213-014-3565-7

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