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: Jiujiu Yu, Hajime Nagasu, Tomohiko Murakami, Hai Hoang, Lori Broderick, Hal M Hoffman, Tiffany Horng
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 43 Pg. 15514-9 (Oct 28 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25313054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aim2 protein, mouse
• Carrier Proteins
• DNA-Binding Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Ubiquitin-Protein Ligases
• parkin protein
• Caspase 1

Topics

• Animals
• Apoptosis
• Carrier Proteins (metabolism)
• Caspase 1 (metabolism)
• Cryopyrin-Associated Periodic Syndromes (enzymology, pathology)
• DNA-Binding Proteins (metabolism)
• Humans
• Inflammasomes (metabolism)
• Mice, Inbred C57BL
• Mitochondria (metabolism, pathology)
• Mitochondrial Membranes (metabolism)
• Mitophagy
• NLR Family, Pyrin Domain-Containing 3 Protein
• Permeability
• Signal Transduction
• Ubiquitin-Protein Ligases (metabolism)