TSPO upregulation in bipolar disorder and concomitant downregulation of mitophagic proteins and NLRP3 inflammasome activation

Abstract

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.

Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

“…The proteins included were those of the electron transport chain (ETC)-complex I subunits (NDUFV1, NDUFV2, NDUFS1), complex II subunit SDHA and complex IV subunit COX2; apoptosis-BAX, Bcl-2, CASP3, mitochondrial fission/fusion-OPA1, MFN1, Drp1, FIS1 and autophagy-Beclin1, p62. Most of the included proteins were reported abnormal in one or both disorders [31][32][33][34][35][36][37][38] . By comparing mitochondrial parameters with and without drug treatment, a specific profile of the effect of each of the drugs was obtained (Fig.…”

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

“…146 By drawing on the concept of mitochondrial quality control, recent studies have demonstrated that patients with BD present an imbalance in mitochondrial fission and fusion toward fission, followed by a decrease in the levels of mitophagy proteins and increase in caspase-3 protein levels in peripheral blood mononuclear cells, suggesting that, in patients with BD, the number of damaged mitochondria exceeds the capacity of mitophagy, and apoptosis becomes the dominant pathway to minimize tissue damage. 147,148 Moreover, numerous studies have provided evidence of increased ROS production and oxidative stress in patients with BD. Replicated evidence has documented alterations in multiple aspects of oxidative stress regulation, including the production of ROS and reduced antioxidant capacity.…”

“… 146 By drawing on the concept of mitochondrial quality control, recent studies have demonstrated that patients with BD present an imbalance in mitochondrial fission and fusion toward fission, followed by a decrease in the levels of mitophagy proteins and increase in caspase-3 protein levels in peripheral blood mononuclear cells, suggesting that, in patients with BD, the number of damaged mitochondria exceeds the capacity of mitophagy, and apoptosis becomes the dominant pathway to minimize tissue damage. 147 , 148 …”

VDAC1 and the TSPO: Expression, Interactions, and Associated Functions in Health and Disease States

“…It has also been shown that in peripheral mononuclear cells (PBMCs) of bipolar disorder (BD) patients, both TSPO and VDAC mRNA and protein expression levels were highly increased, relative to their levels in healthy controls [106]. Moreover, the ratio of TSPO to VDAC was greater in BD than that in healthy controls [106].…”

“…It has also been shown that in peripheral mononuclear cells (PBMCs) of bipolar disorder (BD) patients, both TSPO and VDAC mRNA and protein expression levels were highly increased, relative to their levels in healthy controls [106]. Moreover, the ratio of TSPO to VDAC was greater in BD than that in healthy controls [106]. In addition, it has been shown that the increase in mitochondrial ROS induced by an increase in the TSPO:VDAC1 ratio may activate protein kinase-Cε (PKCε) through the Raf-1-MEK1/2-ERK1/2 pathway, promoting the expression of TSPO [107].…”