Background: Inflammation in central nerve system (CNS) is involved in onset and exacerbation of neurodegenerative diseases. Microglia play an important role in the CNS as main immune cells. We have reported that mitochondrial dysfunction by rotenone, an electron transporter chain I inhibitor, enhanced lipopolysaccharide (LPS)-induced interferon-β (IFN-β) production in microglia. However, the molecular mechanisms remain unclear. Therefore, the current study investigated the influence of mitochondrial dysfunction in intracellular signalings.
Method: BV2 cells, a mouse microglial cell line, were treated by rotenone for 24 hours to impair the mitochondrial function. The expression level of IFN-β was analyzed by real-time PCR and ELISA. The phosphorylated protein level was evaluated by Western blotting. To deplete mitochondrial DNA (mtDNA), BV2 cells were treated with ethidium bromide for 4 days.
Results: Mitochondrial dysfunction enhanced activation of interferon regulatory factor 3 (IRF3) by LPS. In addition, either depletion of mtDNA or treatment with TANK-binding kinase 1 (TBK1) inhibitor significantly blocked the LPS-induced IRF3 phosphorylation and IFN-β production in rotenone-treated BV2 cells.
Conclusions: We found that mitochondrial dysfunction enhanced IFN-β production through mtDNA and TBK1-IRF3 signaling.