The Potential Role of the NLRP3 Inflammasome as a Link between Mitochondrial Complex I Dysfunction and Inflammation in Bipolar Disorder

Figure 1

Mitochondrial complex I dysfunction in patients with BD could lead to increased release of superoxide anions, resulting in greater reactive oxygen species (ROS) production. This release of ROS causes a conformational change in NLRP3 such that the pyrin domain (PYD) becomes available recruit ASC. The combining of NLRP3 and ASC that allows for the recruitment of caspase 1 (csp1) through ASC’s CARD domain, causing the formation of the NLRP3 inflammasome. The inflammasome then migrates to the mitochondria, allowing it to be close to the site of damage. Activated NLRP3 inflammasome releases caspase 1 into the cytosol, which then cleaves and activates two downstream cytokines, Il-1beta and Il-18, causing them to be released into the extracellular space. These two cytokines cause the activation of downstream pathways, which may differ depending on the type of immune cell. Indeed, NLRP3 inflammasome activation may underlie the different patterns of cytokine activation observed in the brain and peripheral samples of patients with BD, where alterations in cytokines pertaining to the IL-1 pathway have been reported for the brain, while a more general pattern of cytokine activation involving IL-6 and TNF-alpha has been reported in the periphery. Cytokine activation in the periphery can lead to various immune disorders, including cardiovascular disease and diabetes, while, in the brain, it could lead to alterations in neurotransmitters and neurodegeneration.