Details

Autor(en) / Beteiligte

• Yu, Jiujiu
• Nagasu, Hajime
• Murakami, Tomohiko
• Hoang, Hai
• Broderick, Lori
• Hoffman, Hal M.
• Horng, Tiffany

Titel

Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-10, Vol.111 (43), p.15514-15519

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 nucleotidebinding 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.