Defective mitochondrial fission augments NLRP3 inflammasome activation.

Ji-Hee Won,Je-Wook Yu,Heung Kyu Lee,Inhwa Hwang,Sangjun Park,Sujeong Hong

doi:10.1038/srep15489

Abstract

Despite the fact that deregulated NLRP3 inflammasome activation contributes to the pathogenesis of chronic inflammatory or metabolic disorders, the underlying mechanism by which NLRP3 inflammasome signaling is initiated or potentiated remains poorly understood. Much attention is being paid to mitochondria as a regulator of NLRP3 inflammasome activation, but little is known about the role of mitochondrial dynamics for the inflammasome pathway. Here, we present evidence that aberrant mitochondrial elongation caused by the knockdown of dynamin-related protein 1 (Drp1) lead to a marked increase in NLRP3-dependent caspase-1 activation and interleukin-1-beta secretion in mouse bone marrow-derived macrophages. Conversely, carbonyl cyanide m-chlorophenyl hydrazone, a chemical inducer of mitochondrial fission, clearly attenuated NLRP3 inflammasome assembly and activation. Augmented activation of NLRP3 inflammasome by mitochondrial elongation is not resulted from the increased mitochondrial damages of Drp1-knockdown cells. Notably, enhanced extracellular signal-regulated kinase (ERK) signaling in Drp1-knockdown macrophages is implicated in the potentiation of NLRP3 inflammasome activation, possibly via mediating mitochondrial localization of NLRP3 to facilitate the assembly of NLRP3 inflammasome. Taken together, our results provide a molecular insight into the importance of mitochondrial dynamics in potentiating NLRP3 inflammasome activation, leading to aberrant inflammation.

Highlights

Mitochondria are dynamic organelles that continuously fuse and divide to control their size, morphology, mtDNA integrity, and cellular redox state[11]
In agreement with previous reports, shDrp[1] cells containing elongated mitochondria exhibited significantly decreased apoptosis and caspase-3 processing compared to shScr bone marrow-derived macrophages (BMDMs) upon TNF-α -cycloheximide (TC) stimulation (Fig. 1d)[21,22]
Considering that inflammasome-mediated neuroinflammation significantly contributes to the pathogenesis of neurodegenerative diseases like Alzheimer’s disease[39], it is of great significance to decipher the role of dynamin-related protein 1 (Drp1)-mediated defective mitochondrial dynamics in inflammasome signaling

Summary

Introduction

Mitochondria are dynamic organelles that continuously fuse and divide to control their size, morphology, mtDNA integrity, and cellular redox state[11]. An imbalance in mitochondrial dynamics, caused by loss-of-function mutations in proteins that make up the mitochondrial fission and fusion machinery, results in the impairment of mitochondrial or cellular functions such as energy production, mtDNA integrity, and cell proliferation, and causes many complex disorders including Parkinson’s or Alzheimer’s disease[11,12]. On the contrary, revealed that mitochondrial elongation is required for MAVS signaling in an Mfn1-dependent manner[14,15]. These findings indicate that mitochondrial fusion facilitates type I interferon (IFN) production in response to virus infection. We attempted to investigate whether altered mitochondrial dynamics due to knockdown of Drp[1] could modulate the assembly and activation of the NLRP3 inflammasome

Methods

Results

Conclusion