Mitochondria as Inducers of Neutrophil Extracellular Traps

Neutrophil extracellular traps (NETs) represent a critical immune defense mechanism that can become pathological in sterile inflammation. Mitochondrial damage-associated molecular patterns (mtDAMPs) emerge as particularly potent triggers of NET formation due to their bacterial-like molecular features inherited from endosymbiotic origins. This review examines the mechanisms by which key mtDAMPs, including mitochondrial DNA, ATP, cardiolipin, cytochrome c, succinate, heme and formylated peptides, induce NETosis through pattern recognition receptors typically reserved for pathogen detection. We describe the complex signaling networks downstream of mtDAMP recognition, highlighting the roles of membrane and intracellular receptors and mitogen-activated protein kinase pathways in orchestrating mtDAMP-induced NET formation. The clinical relevance of mtDAMP-induced NETosis is explored across trauma and wound healing contexts, where neutrophil phenotype along with concentration-dependent and temporal dynamics determine beneficial versus pathological outcomes. Current therapeutic approaches modulating NET formation are discussed challenges in stimulus specificity, pathway redundancy, and use of analgesics and anti-inflammatory drugs. We conclude with future research priorities that include establishing clinically relevant concentration thresholds, elucidating synergistic mtDAMP effects, and developing targeted therapeutic strategies for NET-mediated pathology in sterile inflammatory conditions.