The interplay between inflammation, stress and mitochondria in Bipolar Disorder

Abstract

Bipolar disorder (BP)is a heterogeneous and multifactorial disease. The pathophysiology of BP involves several biological pathways, including the interaction of molecular, cellular, and behavioural mechanisms with susceptibility genes, environmental stressors, and biochemical mechanisms. Therefore, this study aimed to evaluate the crossroads of mitochondrial dysfunction and inflammation and their impact on clinical outcomes in BD patients. Twenty-five BD patients and 25 healthy controls were enrolled for this study. PBMCs were used to measure mitochondria quality control (MQC), apoptosis, and NLRP3 inflammasome-related proteins. DNA was isolated from plasma, and cell-free-mtDNA was evaluated by qPCR. Binary logistic regression analysis with the elimination of nonsignificant covariates was performed with the BD diagnosis as the dependent variable. After controlling for confounders, One-Way ANCOVA showed a downregulation of Mfn2, Opa1, Parkin, p62/SQSTM1, and LC3 and an up-regulation of Fis1 levels, followed by an increase in the active caspase-3 levels and plasma cell-free-mtDNA in BD. Moreover, we observed an up-regulation of NLRP3-related proteins and higher levels of IL-1β and IL-18 in BD. Our study also highlighted the significant correlation between alterations in mitochondrial proteins and inflammatory markers with a decrease in functional status and an increase in the severity of symptoms. Taken together, we suggested that in BD patients, the number of damaged mitochondria exceeds the capacity of mitophagy, causing apoptosis to become the dominant pathway. The lack of mitophagy leads to a loss of MQC, resulting in a release of mtDNA fragments into the circulation and NLRP3 inflammasome activation.