Injury triggers a systemic inflammatory response syndrome (SIRS), similar to sepsis, by releasing mitochondrial damage-associated molecular patterns (DAMPs) into the bloodstream. These mitochondrial DAMPs (MTD), including formyl peptides and mitochondrial DNA (mtDNA), activate innate immunity through pattern recognition receptors (PRRs), such as formyl peptide receptor-1 (FPR1) and TLR9. MTD induce calcium flux and MAP kinase phosphorylation in neutrophils (PMN), leading to PMN migration, degranulation, and organ injury. The release of MTD from injured cells mimics bacterial pathogen-associated molecular patterns (PAMPs), activating similar innate immune pathways and causing a sepsis-like state. Trauma, a leading cause of premature death, activates PMN, leading to organ failure and susceptibility to infection. MTD are mobilized by trauma and enter the circulation, contributing to systemic inflammation. MTD activate PMN through FPR1 and TLR9, leading to increased intracellular calcium, MAP kinase activation, and PMN chemotaxis. MTD also induce the release of matrix metalloproteinase-8 (MMP-8) and interleukin-8 (IL-8) from PMN, promoting tissue damage and inflammation. In vivo, MTD injection causes neutrophil infiltration and organ injury, similar to sepsis. mtDNA activates PMN via TLR9, leading to p38 MAPK activation and IL-8 release. These findings suggest that mitochondrial DAMPs play a key role in trauma-induced inflammation and SIRS, linking trauma, inflammation, and sepsis through the release of MTD. The study highlights the importance of mitochondrial DAMPs in triggering innate immune responses and the potential for targeting these pathways in trauma care.Injury triggers a systemic inflammatory response syndrome (SIRS), similar to sepsis, by releasing mitochondrial damage-associated molecular patterns (DAMPs) into the bloodstream. These mitochondrial DAMPs (MTD), including formyl peptides and mitochondrial DNA (mtDNA), activate innate immunity through pattern recognition receptors (PRRs), such as formyl peptide receptor-1 (FPR1) and TLR9. MTD induce calcium flux and MAP kinase phosphorylation in neutrophils (PMN), leading to PMN migration, degranulation, and organ injury. The release of MTD from injured cells mimics bacterial pathogen-associated molecular patterns (PAMPs), activating similar innate immune pathways and causing a sepsis-like state. Trauma, a leading cause of premature death, activates PMN, leading to organ failure and susceptibility to infection. MTD are mobilized by trauma and enter the circulation, contributing to systemic inflammation. MTD activate PMN through FPR1 and TLR9, leading to increased intracellular calcium, MAP kinase activation, and PMN chemotaxis. MTD also induce the release of matrix metalloproteinase-8 (MMP-8) and interleukin-8 (IL-8) from PMN, promoting tissue damage and inflammation. In vivo, MTD injection causes neutrophil infiltration and organ injury, similar to sepsis. mtDNA activates PMN via TLR9, leading to p38 MAPK activation and IL-8 release. These findings suggest that mitochondrial DAMPs play a key role in trauma-induced inflammation and SIRS, linking trauma, inflammation, and sepsis through the release of MTD. The study highlights the importance of mitochondrial DAMPs in triggering innate immune responses and the potential for targeting these pathways in trauma care.