Blocking reverse electron transfer-mediated mitochondrial DNA oxidation rescues cells from PANoptosis

Area of Science:

• Cell Death Biology
• Immunology
• Mitochondrial Biology

Background:

• PANoptosis is a novel cell death pathway implicated in inflammatory diseases.
• Mitochondrial reactive oxygen species (mtROS) generated via reverse electron transport (RET) contribute to pyroptosis and necroptosis.
• The role of mtROS and RET in PANoptosis remains to be fully elucidated.

Purpose of the Study:

• To investigate the role of mtROS and RET in PANoptosis.
• To explore the therapeutic potential of anti-RET reagents in inhibiting PANoptosis.

Main Methods:

• PANoptosis was induced in macrophages using a TGF-β-activated kinase 1 (TAK1) inhibitor (5Z-7-oxozeaenol) plus lipopolysaccharide (LPS).
• The effects of anti-RET reagents (1-methoxy PMS and dimethyl fumarate) on PANoptosis, mtROS production, and PANoptosome formation were assessed.
• An HLH mouse model was utilized to evaluate the in vivo efficacy of anti-RET reagents.

Main Results:

• Pretreatment with anti-RET reagents (MPMS or DMF) dose-dependently inhibited Oxo/LPS-induced PANoptosis in macrophages.
• MPMS and DMF suppressed all three arms of PANoptosis signaling and PANoptosome formation.
• RET and mtROS were induced by Oxo/LPS, and this was reversed by MPMS/DMF, which also blocked mtROS and PANoptosome formation.
• Anti-RET reagents alleviated HLH lesions in mice, reducing PANoptosis markers in the liver and kidney.

Conclusions:

• RET and mitochondrial DNA oxidation are critical inducers of PANoptosis.
• Anti-RET reagents (MPMS, DMF) represent a novel class of PANoptosis inhibitors.
• These findings highlight the potential of anti-RET strategies for treating inflammatory diseases associated with PANoptosis.