Lithium reduces the effects of rotenone-induced complex I dysfunction on DNA methylation and hydroxymethylation in rat cortical primary neurons.
BACKGROUND
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.
Department of Psychiatry, University of Toronto, Medical Science Building, Room 4204, 1 king's College Circle, Toronto, ON, M5S 1A8, Canada.
Gustavo
G
Scola
Helena K
HK
Kim
L Trevor
LT
Young
Mirian
M
Salvador
Ana C
AC
Andreazza
D044503:5-Methylcytosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001714:Bipolar Disorder / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D042967:Electron Transport Complex I / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000494:pharmacology*
D014150:Antipsychotic Agents; D012402:Rotenone; D044503:5-Methylcytosine; D000255:Adenosine Triphosphate; D008094:Lithium; D042967:Electron Transport Complex I