Bipolar disorder (BD) is a chronic, debilitating illness with a global prevalence of up to 4.8%. The importance of understanding how dysfunctional mitochondria and mitophagy contribute to cell survival and death in BD is becoming increasingly apparent. Therefore, the purpose of this study was to evaluate the mitophagic pathway and NLRP3
inflammasome activation in peripheral blood mononuclear cells (PBMCs) of patients with BD and healthy individuals. Since 18-kDa translocator
protein (TSPO) plays an important role in regulating mitochondrial function and since TSPO itself impairs cellular mitophagy, we also investigated the changes in the TSPO-related pathway. Our results showed that patients with BD had lower levels of Parkin, p62/SQSTM1 and LC3A and an upregulation of TSPO pathway
proteins (TSPO and VDAC), both in terms of
mRNA and
protein levels. Additionally, we found a negative correlation between mitophagy-related
proteins and TSPO levels, while VDAC correlated negatively with p62/SQSTM1 and LC3
protein levels. Moreover, we found that the gene expression levels of the NLRP3-related
proteins NLRP3, ASC, and pro-casp1 were upregulated in BD patients, followed by an increase in caspase-1 activity as well as IL-1β and
IL-18 levels. As expected, there was a strong positive correlation between NLRP3-related
inflammasome activation and TSPO-related
proteins. The data reported here suggest that TSPO-VDAC complex upregulation in BD patients, the simultaneous downregulation of mitophagic
proteins and NLRP3
inflammasome activation could lead to an accumulation of dysfunctional mitochondria, resulting in
inflammation and apoptosis. In summary, the findings of this study provide novel evidence that
mitochondrial dysfunction measured in peripheral blood is associated with BD.