S shown that oxidized mtDNA is 2883-98-9 chemical information actually required to activate NLRP3. This finding is provocative because it suggests that mtDNA is released from mitochondria without release of cytochrome c and induction of cell death. Further study of this observation is likely to reveal new mitochondrial transport mechanisms. Another recent finding linking mitochondria to NLRP3 is the observation that cardiolipin on the mitochondrial outer membrane directly binds to NLRP3 resulting in its activation. Importantly, although many studies suggest an important role of mitochondrial ROS, cardiolipin and DNA for in regulating NLRP3 activation, direct genetic evidence is still lacking in vivo. It is important to note that mitochondrial ROS are necessary for optimal activation of NLRP3 inflammasome as other key activators such as influx of calcium and potassium efflux are also major regulators of NLRP3 inflammasome. Calcium influx also contributes to mitochondrial damage which might increase mitochondrial ROS and release of mitochondrial DNA to amplify NLRP3 inflammasome activation. The specific mechanisms by which diverse PAMPs and DAMPs increase mitochondrial ROS and by which mitochondrial ROS and ions such as calcium cooperate to optimally activate NLRP3 have yet to be delineated. Immunity. Author manuscript; available in PMC 2016 March 17. Author Manuscript Author Manuscript Author Manuscript Author 
Manuscript Weinberg et al. Page 7 An emerging theme in the past decade is that the mitochondrial outer membrane serves as a signaling platform for innate immune responses. The most studied example of this is a class of PRRs that respond to viral infection known as the retinoic-acid-inducible protein I like receptor family. The three members of RLRs are RIG-I, MDA5 and DHX58 that function in antiviral immunity by MedChemExpress DMXB-A sensing viral 5-triphosphorylated and uncapped single- or double-stranded RNA resulting in the production of type I interferons and proinflammatory cytokines. A breakthrough in establishing the role for mitochondria in RLR-activated antiviral immunity was the identification of the RLR mitochondrial adaptor protein MAVS localization to the outer mitochondrial membrane is indispensable for its function. MAVS contains a C-terminal transmembrane domain, which targets the protein to the outer membrane of mitochondria. Subsequent studies demonstrated that MAVS does not bind to free mitochondria but to mitochondrial associated membrane, which physically connects ER specialized domain to outer mitochondrial membrane. MAM provides a mitochondrialER inter-organelle communication that regulates stress and metabolic signaling. Mice deficient in MAVS are impaired in their ability to produce type I IFNs thus are highly susceptible to RNA virus infection. RIG-I and MDA5 interact with MAVS through mutual caspase activation and recruitment domains upon recognition of viral RNA. Subsequently, RIG-I interaction with MAVS induces prion-like aggregates of MAVS on the outer mitochondrial membrane leads to activation of downstream pathways such as interferon regulatory factor 3, MAP kinases, and nuclear factor-B . It is important to note that MAVS is also localized to the membranes of peroxisomes, which is necessary for the rapid early but transient expression of antiviral genes called PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19846797 interferonstimulated genes . Furthermore, mitochondrial MAVS induces both IFN-b and IFN- while peroxisomal MAVS induces IFN- in a interferon regulatory factor 1 dependent manner. Thus, maximal a.S shown that oxidized mtDNA is actually required to activate NLRP3. This finding is provocative because it suggests that mtDNA is released from mitochondria without release of cytochrome c and induction of cell death. Further study of this observation is likely to reveal new mitochondrial transport mechanisms. Another recent finding linking mitochondria to NLRP3 is the observation that cardiolipin on the mitochondrial outer membrane directly binds to NLRP3 resulting in its activation. Importantly, although many studies suggest an important role of mitochondrial ROS, cardiolipin and DNA for in regulating NLRP3 activation, direct genetic evidence is still lacking in vivo. It is important to note that mitochondrial ROS are necessary for optimal activation of NLRP3 inflammasome as other key activators such as influx of calcium and potassium efflux are also major regulators of NLRP3 inflammasome. Calcium influx also contributes to mitochondrial damage which might increase mitochondrial ROS and release of mitochondrial DNA to amplify NLRP3 inflammasome activation. The specific mechanisms by which diverse PAMPs and DAMPs increase mitochondrial ROS and by which mitochondrial ROS and ions such as calcium cooperate to optimally activate NLRP3 have yet to be delineated. Immunity. Author manuscript; available in PMC 
2016 March 17. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Weinberg et al. Page 7 An emerging theme in the past decade is that the mitochondrial outer membrane serves as a signaling platform for innate immune responses. The most studied example of this is a class of PRRs that respond to viral infection known as the retinoic-acid-inducible protein I like receptor family. The three members of RLRs are RIG-I, MDA5 and DHX58 that function in antiviral immunity by sensing viral 5-triphosphorylated and uncapped single- or double-stranded RNA resulting in the production of type I interferons and proinflammatory cytokines. A breakthrough in establishing the role for mitochondria in RLR-activated antiviral immunity was the identification of the RLR mitochondrial adaptor protein MAVS localization to the outer mitochondrial membrane is indispensable for its function. MAVS contains a C-terminal transmembrane domain, which targets the protein to the outer membrane of mitochondria. Subsequent studies demonstrated that MAVS does not bind to free mitochondria but to mitochondrial associated membrane, which physically connects ER specialized domain to outer mitochondrial membrane. MAM provides a mitochondrialER inter-organelle communication that regulates stress and metabolic signaling. Mice deficient in MAVS are impaired in their ability to produce type I IFNs thus are highly susceptible to RNA virus infection. RIG-I and MDA5 interact with MAVS through mutual caspase activation and recruitment domains upon recognition of viral RNA. Subsequently, RIG-I interaction with MAVS induces prion-like aggregates of MAVS on the outer mitochondrial membrane leads to activation of downstream pathways such as interferon regulatory factor 3, MAP kinases, and nuclear factor-B . It is important to note that MAVS is also localized to the membranes of peroxisomes, which is necessary for the rapid early but transient expression of antiviral genes called PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19846797 interferonstimulated genes . Furthermore, mitochondrial MAVS induces both IFN-b and IFN- while peroxisomal MAVS induces IFN- in a interferon regulatory factor 1 dependent manner. Thus, maximal a.