Meta-Biol

• Pathways

Gasdermin D (GSDMD) is cleaved by inflammatory caspases (CASP) downstream of inflammasome activation (Shi J et al. 2015). The released N‑terminal fragment of GSDMD (1‑275) targets the plasma membrane to drive pyroptosis. In addition, GSDMD (1‑275) can bind to and permeabilize liposomes containing cardiolipin, a phospholipid found on the mitochondrial membrane and bacterial membranes (Ding J et al. 2016; Liu X et al. 2016). Although cardiolipin is primarily located in the inner mitochondrial membrane, the outer mitochondrial membrane also contains around 10‑20% cardiolipin and cardiolipin has been shown to translocate in a regulatable manner between the compartments (Liu et al. 2003; reviewed in Dudek J 2017). Further, upon expression in human embryonic kidney 293T (HEK293T) cells, GSDMD (1‑275) induces cytochrome c (CYCS) release from the mitochondria leading to the CASP3 activation (Rogers C et al. 2019). In a mouse model of inflammatory lung injury, lipopolysaccharide (LPS) triggered caspase‑11‑mediated cleavage of mouse GSDMD, which formed pores on the mitochondrial membrane and induced mitochondrial DNA (mtDNA) release into the cytosol of endothelial cells (Huang LS et al. 2020). Moreover, single‑cell analysis of pyroptosis dynamics in mouse macrophages revealed that GSDMD disrupts the mitochondrial membrane potential and leads to mitochondrial decay that precedes pyroptotic cell lysis (de Vasconcelos NM et al. 2019). These data suggest that the N‑terminal fragment of GSDMD binds mitochondrial cardiolipin and forms pores triggering the release of mitochondrial proteins and DNA, however, the physiological relevance of this event remains to be determined.

This Reactome event describes the GSDMD (1‑275) binding to mitochondrial cardiolipin leading to CYCS release.