Macrophages play a crucial role in both innate immunity and inflammation. The NAIP/NLRC4

inflammasome is an immune sensor that detects virulence factors from invasive Gram-negative

bacteria, including flagellin and type III secretion system (T3SS) proteins, to trigger pyroptotic

cell death. Mitochondria are emerging as important regulators of inflammasome signaling;

however, their contribution to NLRC4 activation remains unclear. Here, we show that

mitochondria serve as essential platforms for NAIP/NLRC4 inflammasome assembly and

activation in macrophages. Mitochondrial depletion in mouse immortalized bone marrow-derived

macrophages (iBMDMs) significantly impairs ASC speck formation and NLRC4 inflammasome

activation. NLRC4 activation in mouse BMDMs lacking mitochondrial transcription factor A

(TFAM) was also diminished. Upon activation by Salmonella or EprJ (a rod protein of E. coli

T3SS), NLRC4, ASC, and Caspase-1 are recruited to mitochondria in a time-dependent manner

in mouse BMDMs. NLRC4 activation subsequently induces mitochondrial dysfunction through

Caspase-1- and Caspase-8-mediated cleavage of the pro-apoptotic factor BID, serving as a

positive feedback loop between mitochondrial damage and inflammasome signaling that further

amplifies the inflammasome response. Our findings reveal a critical interplay between

mitochondria and inflammasomes, providing new insights into host–pathogen interactions and

suggesting potential strategies for targeting inflammasome-related diseases.

This content is only available as a PDF.
2025
Sign in via your Institution