title: Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy.
abstract: Inflammasomes are intracellular sensors that couple detection of pathogens and cellular stress to activation of Caspase-1, and consequent IL-1β and IL-18 maturation and pyroptotic cell death. Here, we show that the absent in melanoma 2 (AIM2) and nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes trigger Caspase-1-dependent mitochondrial damage. Caspase-1 activates multiple pathways to precipitate mitochondrial disassembly, resulting in mitochondrial reactive oxygen species (ROS) production, dissipation of mitochondrial membrane potential, mitochondrial permeabilization, and fragmentation of the mitochondrial network. Moreover, Caspase-1 inhibits mitophagy to amplify mitochondrial damage, mediated in part by cleavage of the key mitophagy regulator Parkin. In the absence of Parkin activity, increased mitochondrial damage augments pyroptosis, as indicated by enhanced plasma membrane permeabilization and release of danger-associated molecular patterns (DAMPs). Therefore, like other initiator caspases, Caspase-1 activation by inflammasomes results in mitochondrial damage.
authors.affiliation: Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Jiujiu
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Hajime
authors.initials: H
authors.lastname: Nagasu
authors.affiliation: Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Hai
authors.initials: H
authors.lastname: Hoang
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and Rady Children's Hospital, San Diego, CA 92123.
authors.forename: Lori
authors.initials: L
authors.lastname: Broderick
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and Rady Children's Hospital, San Diego, CA 92123.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115; thorng@hsph.harvard.edu.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Horng
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000201:enzymology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D063306:Mitophagy; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010539:Permeability; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020170:Caspase 1
keywords: inflammasomes; mitochondrial damage; mitophagy; pyroptosis