Although systemic inflammatory response syndrome (SIRS) is commonly associated with pathogenic infection, certain patients with SIRS do not suffer from such infection, thus reflecting poor understanding of its pathophysiology (1). Therefore, other factors may also serve a key role in the occurrence and development of SIRS.

Stimulating adaptive immune response pattern recognition receptors (PRRs) is associated with development of SIRS. PRRs are derived from pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) of exogenous and endogenous invaders, respectively (2). Among known DAMPs, mitochondrial DAMPs (mtDAMPs), including mitochondrial DNA (mtDNA), N-formyl peptides (NFPs), mitochondrial transcription factor (TFAM), cardiolipin and ATP (3), have attracted increasing attention from researchers. The aforementioned molecules are considered to be danger signals released in response to tissue injury, thus triggering an immune response similar to that induced by pathogens (2). Previous studies have shown that plasma levels of mtDAMPs may be associated with clinical outcome of septic shock, major surgery or severe trauma (4–6). In addition, it has been suggested that mtDNA may be a more efficient biomarker than lactate concentration/sequential organ failure assessment score in predicting mortality rate in patients with sepsis following emergency admission (7). However, mtDNA has not been widely used in clinical practice to optimize clinical treatment. Therefore, further research is urgently required.

The present review aimed to summarize the effects and mechanisms of mtDAMPs on activation of inflammatory responses and development of SIRS. Although multiple types of mitochondrial component and metabolites, such as mtDNA, NFPs, TFAM, transcription factor A, ATP, cardiolipin, cytopigment C, succinate and mitochondrial RNA serve as DAMPs (8), the present review focused on widely studied mitochondria-derived DAMPs, such as mtDNA, NFPs and TFAM. Additionally, the present review focused on the mechanisms underlying the effects of the aforementioned DAMPs on inducing sepsis-like responses and their potential clinical value.

Mitochondria, the ‘cellular energy factories’, are organelles in eukaryotic cells, which comprise ~25% of the total cytoplasm volume. Mitochondria are complex organelles due to their unique evolutionary history and components, as well as their genome (9). Additionally, mitochondria are involved in a range of cell fate decisions, including energy metabolism, reactive oxygen species (ROS) formation, calcium homeostasis, cell proliferation and apoptosis (10). When mitochondrial homeostasis is disrupted and the apoptosis pathway is activated under severe stress conditions, including cytoskeleton alteration, extensive DNA damage, endoplasmic reticulum (ER) and replication stress, sustained ROS burst, calcium overload and mitotic defect, mitochondrial outer membrane permeabilization is targeted by the aforementioned stressors (11). The activation of the pro-apoptotic pathway regulates the structure of pro-apoptotic proteins BAX and Bcl2 homologous antagonist/killer (12). In addition, it permeabilizes the outer membrane of mitochondria to allow transport of pro-apoptotic molecules from the inner membrane into the cytosol to initiate a caspase cascade, resulting in rapid cell death (13). It has also been reported that the mitochondrial intermembrane space proteins, such as cytochrome c, which are released into the cytoplasm following increased membrane permeability, also mediate activation of apoptotic proteases (14). Displaced mtDAMPs have been identified following cell death or mitochondrial dyshomeostasis in patients with trauma, intestinal ischemia/reperfusion and lung injury (1,15–19). Therefore, it has been hypothesized by clinicians that mitochondria serve a vital role in catalyzing the pathophysiology of sterile inflammation following trauma (1).

Mitochondria produce ATP via oxidative phosphorylation; ROS are byproducts of this process (1). Therefore, mitochondria are the primary source of ROS; ATP and ROS are also considered to be DAMPs. Damage-induced mitochondrial secretion of ATP increases local levels of ATP, thereby promoting macrophage-mediated death of sepsis-causing bacteria via P2X7 and P2X4 receptors (20,21). Emerging evidence has suggested that under physiological conditions, cells produce mitochondrial components that are not actively secreted into the cytoplasm; however, these components are released via cellular disruption (18,22–24).

Human mtDNA is a 16,569-bp long superhelical closed-loop double-stranded DNA molecule that encodes essential protein subunits of the oxidative phosphorylation system, including the electron transport chain (complex I–IV) and ATP synthase (complex V), which drive oxidative phosphorylation and ATP production. Apart from the nucleus, mitochondria are the only source of DNA in cells (9,25). Unlike nuclear DNA, mtDNA is more prone to injury and lacks repair systems (26). It has been suggested that mitochondria originated from gram-negative (G⁻) bacteria. Following phagocytosis of G-bacteria by eukaryotes, the bacteria may have formed a symbiotic association with the host and gradually evolved into mitochondria (25). Due to this evolutionary homology, mitochondria are similar to bacteria; both exhibit conserved hypomethylated 5′-cytosine-phosphoguanine (CpG) gene sequences and pro-inflammatory effects (9,27). Following cell injury, these endogenous mitochondrial ‘enemies’ are recognized by classical PRRs to induce immune responses, thereby acting as a bridge between trauma, inflammation and SIRS (9).

In critical patients with multiple organ dysfunction syndrome (MODS) and sepsis, mitochondrial dysfunction may lead to energetic and metabolic failure in white blood cells, thus altering their function and attenuating the ability of the host to fight infection (28). mtDNA is more susceptible to damage compared with nuclear DNA since it lacks introns and histones (29).

mtDNA damage affects the respiratory chain, enhances oxidative stress and inflammatory responses, and induce apoptosis, leading to cell dysfunction and tissue damage, which further aggravate mitochondrial dysfunction in cells, thus forming a feedback loop (30). Therefore, mtDNA is considered to be a trigger that stimulates the innate immune response (15). In 2013, Nakahira et al (31) published the first clinical trial in this area, including 200 patients from medical Intensive Care Units. The aforementioned study showed that circulating mtDNA was significantly increased in patients who died within 28 days of admission compared with those who survived. In addition, mtDNA was positively associated with mortality in patients who were hospitalized for up to 28 days. Further studies confirmed these results (32–35). Additionally, other studies have suggested that mtDNA serves a key role in the pathogenesis of severe trauma, major abdominal surgery, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), ischemia/reperfusion (I/R) injury, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), myocarditis and myocardial infarction (1,15,19,36–38).

During mitochondrial stress, mitochondrial membrane potential is decreased, leading to impaired membrane integrity (39,40). These changes facilitate leakage of mtDNA into the cytosol. mtDNA exhibits immunological potential and is a key DAMP. Stimulators of interferon genes (STING) is produced following activation of toll-like receptor 9 (TLR9), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS) and other signaling pathways, thereby promoting the occurrence and development of SIRS by regulating the innate immune response and contribute to inflammation initiation (25,41). The potential pathophysiological mechanisms are illustrated in Fig. 1.

NFP is a potent chemotactic polypeptide synthesized in mitochondria (23). In the absence of cellular damage, bacteria-like NFPs are isolated within the mitochondria; however, during severe trauma and cell death, NFPs are released into the blood circulation to activate the chemokine formyl peptide receptor (FPR), which recruits immune cells and promotes inflammatory responses (63). FPR comprises conserved G-protein-coupled receptors that serve a key role in host defense and inflammatory responses (64). FPR1, FPR2/lipoxygenase A4 receptor and FPR3 have been identified in humans (1). These receptors are expressed in multiple types of cell, with the highest expression levels of FPR1 and FPR2 observed in neutrophils, and those of FPR3 in monocytes/macrophages (64). A number of structurally and chemically different ligands (such as microbial origins peptides, endogenous peptides and synthetic small molecules) activate FPRs (64), while NFP is the only common ligand for all three receptors in humans (65).

Wenceslau et al (66) showed that mitochondrial FPs (mtFPs) caused inflammation and vascular dysfunction via FPRs, and accelerated the development of sepsis. Another study revealed that mtFPs could cause sepsis-like syndrome, heart failure, heatstroke, vascular leakage, thrombosis and lung injury in a rat model, suggesting that NFPs may be a bridge between trauma, SIRS and cardiovascular failure (67). Another clinical study on traumatic hemorrhagic shock-induced lung injury demonstrated that trauma-induced release of NFPs could promote infiltration of neutrophils into the lung, and aggravate SIRS and sepsis (16). This may be because mtFPs-induced FPR activation could cause sepsis-like symptoms, leading to ALI. Dorward et al (68) found increased bronchoalveolar lavage fluid and serum levels of mtFPs in patients with ARDS. FPR1 has been reported to be involved in neutrophil recruitment and alveolar leakage following sterile injury. Previous in vivo and in vitro studies revealed that FPR1 could also be activated in a neutrophil activation-dependent manner, suggesting that pluripotency of FPR1-induced by mtFPs may be the mechanism underlying their inflammatory effect (24,36). Therefore FPR1 may be a potential therapeutic target for treating aseptic ALI.

TFAM is an abundant mitochondrial protein; each mtDNA molecule binds to ~1,000 TFAM molecules. The tight binding of TFAM with mtDNA stabilizes the structure of mtDNA and protects mt function (29,69). When mitochondria are damaged, mtDNA and TFAM are both released into the cytoplasm (17,19). TFAM serves as a pro-inflammatory cell signaling molecule and is recognized by monocytes, leading to enhanced secretion of pro-inflammatory factors such as IL-1β, IL-6 and IL-8 (70). Hepokoski et al (17) showed that pulmonary I/R-mediated lung injury was associated with accumulation of extracellular mtDNA and TFAM, whereas circulating TFAM promoted infiltration of neutrophils in the lung. In addition, West et al (71) indicated that TFAM may serve a key role in maintaining the stability of mtDNA; therefore, when TFAM levels are low, the stability of mtDNA is decreased. This was also confirmed by van der Slikke et al (30); this previous study demonstrated that in sepsis-induced acute kidney damage, the degree of mitochondrial damage was inversely proportional to the expression of TFAM. In conclusion, TFAM may serve a key dual role in the activation of inflammation-associated signaling pathways. Firstly, TFAM could stabilize the structure and function of mtDNA (70), and secondly, as a DAMP, TFAM could also enhance inflammatory responses, similar to other DAMPs, and cause injury to vital organs, such as the lung and kidney (17,70). However, the synergistic effect of TFAM and mtDNA on inflammatory responses requires further investigation.

Intestinal mucosal epithelial cells exhibit a strong metabolism and rapidly proliferate, renewing every 4–5 days (72); therefore, the rate of mitochondrial energy metabolism and the number of mitochondria are increased in these cells compared with other cells (73). Additionally, intestinal epithelium has been reported to be prone to hypoxia; therefore, intestinal I/R can promote both intestinal mucosal epithelial cell and mitochondrial injury, resulting in increased circulating mtDNA levels (74). A previous study showed that oxidized mtDNA could trigger a powerful inflammatory response (15). The aforementioned findings suggested that mtDNA may not only serve as a marker of intestinal I/R injury, but could also be involved in inflammation and cell death.

Just as mtDNA is thought to trigger the innate immune response, the gut is also considered to promote SIRS and multiple organ dysfunction (75). Consistent with previous studies on intestinal I/R injury (15,76), Hu et al (15) demonstrated that mtDNA was associated with increased secretion of inflammatory cytokines and intestinal barrier injury. However, intervention with mitochondrial-targeted antioxidant MitoQ could protect the intestinal barrier during I/R (15,76). It has been reported that several inflammatory cytokines, such as TNF-α, IFN-γ and IL, are involved in regulation of intestinal tight junction integrity (77). TNF-α is a key factor in elevating gut permeability via occludin (OCLN); OCLN overexpression has been shown to mitigate cytokine-mediated increased gut permeability (78). Furthermore, anti-TNF therapy could improve epithelial barrier function (79). Based on the aforementioned studies, it was hypothesized that mtDAMPs and mtDAMP-mediated inflammatory responses could be associated with intestinal barrier function. When the intestinal barrier is damaged, bacterial translocation occurs and products of microorganisms, such as alimentary antigens, may enter the bloodstream, thus intensifying SIRS and promoting the formation of a feedback loop that facilitates development of fatal sepsis (75,80).

Injury-released mtDAMPs serve a key role in the occurrence and development of systemic inflammatory response (1). The inflammatory response exerts a protective effect on the body; however, excessive inflammatory response damages organ function, leading to the occurrence and development of sepsis, MODS and death (81). In addition, mtDAMP-mediated activation of inflammatory signaling pathways can aggravates mitochondrial damage, resulting in release of more mtDAMPs and intestinal barrier dysfunction. The aforementioned processes contribute to the development of SIRS when accompanied by displaced intestinal flora and release of harmful metabolites (15,58). Further studies on mtDAMPs are required to determine whether mtDNA serves as a biomarker for predicting disease severity or mortality, and to determine the mechanism underlying DAMP-induced SIRS pathogenesis and development during mitochondrial injury. Additionally, the effect of drugs on protecting mitochondrial function or antagonizing mtDAMP-associated receptors to interrupt this pathophysiological process should be investigated to support the potential role of mtDAMPs as a significant target for preventing and treating sepsis.