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

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

Research output: Contribution to journalArticle

126 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)15514-15519
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number43
DOIs
StatePublished - Oct 28 2014

Fingerprint

Mitochondrial Degradation
Inflammasomes
Caspase 1
Initiator Caspases
Interleukin-18
Mitochondrial Membrane Potential
Interleukin-1
Melanoma
Reactive Oxygen Species
Nucleotides
Cell Membrane

Keywords

  • Inflammasomes
  • Mitochondrial damage
  • Mitophagy
  • Pyroptosis

ASJC Scopus subject areas

  • General

Cite this

Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. / Yu, Jiujiu; Nagasu, Hajime; Murakami, Tomohiko; Hoang, Hai; Broderick, Lori; Hoffman, Hal M.; Horng, Tiffany.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 43, 28.10.2014, p. 15514-15519.

Research output: Contribution to journalArticle

Yu, Jiujiu ; Nagasu, Hajime ; Murakami, Tomohiko ; Hoang, Hai ; Broderick, Lori ; Hoffman, Hal M. ; Horng, Tiffany. / Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 43. pp. 15514-15519.
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