Interestingly, Sazonova et al
Interestingly, Sazonova et al. production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments. gene develop increased vascular stiffness, hypertrophy of the vascular wall, and renal dysfunction [120]. In addition, increased ONOO? production was detected in LPS-treated mice and this overproduction of Pristinamycin ONOO? was proportional to the developing progression of inflammation [121]. Impaired NO production was also related with enhanced ONOO? production [122]. All Pristinamycin of these factors taken together, a high concentration of ONOO? has been directly linked with severe atherosclerosis damage [123]. 3.2. Mitochondria and NLRP3 Inflammasome Early evidence supporting the relationship between mitochondria and the NLRP3 inflammasome was reported by Zhou et al. [17], demonstrating that mitochondrial ROS are NLRP3 activators. Therefore, antioxidant compounds could block NLRP3 inflammasome assembly and ameliorate inflammation [124]. In addition, impaired mitophagy, a cellular process implicated in mitochondrial renewal, enhances mitochondrial damage and the release of ROS, mtDNA, and K+ into the cytoplasm, which promotes NLRP3 inflammasome activation. In fact, NRLP3 protein can interact directly with released mtDNA, initiating the inflammatory process [19]. Taken together, these findings support the hypothesis that impaired mitochondria could activate inflammation through NLRP3 in a direct way [125]. However, it is still unknown how NLRP3 activators can also induce mitochondrial damage. It is thought that they may alter intracellular Ca2+ homeostasis. One example is ATP, a canonical NLRP3 activator that can induce Ca2+ influx and promote the production of mitochondrial ROS and the loss of m [126]. Furthermore, K+ efflux, caused by mitochondrial damage, can mediate the influx of Ca2+, resulting in a loss of mitochondrial Ca2+ homeostasis Pristinamycin [127]. However, K+ efflux can also activate NLRP3 inflammasome independently of Ca2+ signaling [128]. New studies are required to evaluate the relevance of Ca2+ flux in NLRP3 inflammasome activation and mitochondrial dysfunction. NLRP3 inflammasome can also be activated through the presence of bacterial molecules, such as N-acetylglucosamine, which are able to inhibit and dissociate the glycolytic enzyme hexokinase. Hexokinase is associated with the voltage-dependent anion channel (VDAC) at the mitochondrial outer membrane [129]. The VDAC regulates mitochondrial ROS production [130], can release large molecules (including mtDNA) into the cytosol [131], and is localized to Pristinamycin cardiolipin-rich regions an NLRP3 activator [132]. The interaction of hexokinase with VDAC protects cells from mitochondrial ROS production [130] and inhibits the sustained opening of the mitochondrial permeability transition pore (MPTP) [131]. In addition, metabolic perturbations that inhibit hexokinase function, such as treatment with glucose-6-phosphate, 2-deoxyglucose, or citrate, all lead to inflammasome activation [133]. This evidence indicates the close relationship between metabolic alterations affecting hexokinase function and localization and inflammatory processes. In contrast, several studies have reported another link between mitochondrial damage and NLRP3 activation. Thus, Yu et al. suggested that mitochondrial damage could be a side effect of inflammasome activation and, thereby, a consequence rather than a cause [134]. Additionally, the specific mitochondrial ROS activation mechanism in NLRP3 is still unknown. Despite the fact that ROS scavengers such as N-acetyl-lysine (NAC) reduce the transcription of NLRP3 and pro-IL-1, they have no apparent effect on mitochondrial ROS [135]. Furthermore, ROS generation was not affected in NLRP3?/? cells in response to LPS and ATP treatment, although NLRP3 deficiency was able to prevent PSTPIP1 mitochondrial depolarization [19]. Nevertheless, we are still far from establishing a clear connection between mitochondria and NLRP3. Mitochondria themselves can also contribute to NLRP3 inflammasome formation by acting as an assembly platform. Specifically, MAVS and mitofusin 2 (Mfn2) have been proposed to recruit the NLRP3 protein to mitochondria in response to viral infection or non-mitochondrial NLRP3 activators. In its native form, most of the NLRP3 protein resides on the endoplasmic reticulum (ER). Upon stimulation with NLRP3 inducers, NLRP3 and ASC colocalize with mitochondria-associated ER membranes (MAMs) in the perinuclear space [136]. MAMs are essential in the initiation and regulation of the innate immune system, which includes inflammation [137], in addition to Ca2+ signaling [138]. Zhang et al. [136] described the following process: (1).