Mitochondria in pyroptosis: Mechanisms and implications

Pyroptosis is an inflammatory, necrotic, and lytic form of programmed cell death, involving activation of inflammasome complexes, inflammatory caspases, and the cleavage of gasdermins. Gasdermins are a large family of pore-forming proteins with critical implications in key cellular processes and inflammatory disease contexts. These gasdermins subsequently oligomerize to form pores in the plasma membrane, releasing cellular contents and inflammatory mediators. Mechanistically, pyroptosis can occur via either caspase-1-dependent canonical pathway or the caspase-1-independent non-canonical pathway, both ultimately resulting in similar forms of pyroptotic cell death. While the underlying mechanisms of pyroptosis are broad and complex, certain key processes simplify the understanding of these mechanisms. One such critical process is the role of mitochondria and mitochondrial dysfunction in mediating pre-pyroptotic signaling. This review aims to provide a brief overview of the general mechanisms of pyroptosis, followed by a discussion of the latest findings on the functional and regulatory roles of mitochondria in pyroptosis. Moreover, we aimed to discuss and decipher emerging concepts such as the interaction between gasdermin D and cardiolipin, the role of mitochondrial DNA and its associated signaling pathways, as well as perspectives on the clinical relevance of these findings in conditions like sepsis, cardiotoxicity, and other diseases.