Table 1.
mtDAMPs | Intracellular physiological role | Extracellular actions | Release pathways | Receptors | Implicated diseases |
---|---|---|---|---|---|
mtDNA | Coding for oxidative phosphorylation complex subunits (mitochondrial proteins) | Pro-inflammatory response; neutrophil activation (13, 14) and NET production (14); increase TLR9 expression in macrophages (15); endothelial cells activation (16) promoting neutrophils adhesion and transmigration | TLR9, inflammasomes [NLRP3, AIM2 and NLRC4 (23–25)], STING (26–28) | Sepsis (29–37), trauma (31, 36, 38–43), cardiogenic shock (30, 44), cancer (45–52), liver failure (53, 54), heart failure (55), atherosclerosis (56), strokes (57), rheumatoid arthritis (58, 59), SLE (60–62) | |
ATP | Energy metabolism and coenzyme | Pro-inflammatory response; neutrophil chemotaxis, adhesion (63), phagocytosis (64, 65) and degranulation (66, 67); monocyte migration (68), adhesion (69), ROS production (23, 70, 71) and phagosome lysosome fusion (72); lymphocytes migration (73), activation (74) and proliferation (63); activation of NLRP3 inflammasome on monocytes (75, 76) | Purinergic receptors (P2X and P2Y) | Cancer (80, 81), asthma (82, 83), GVHD (84), lung diseases (85, 86), CF (87) | |
TFAM | Regulation of mtDNA transcription and stabilization | Pro-inflammatory response; synergistic effect with other mt DAMPs (N-formyl peptide and mtDNA) to increase cytokine production in monocytes (88) and dendritic cells (89); increase cytokines production in macrophages (90) |
|
Unknown | Heat failure (91), COPD (92) |
N-formyl peptide (fMLP) | Share similarities with bacterial N-formyl peptide | Pro-inflammatory response; chemoattractant for neutrophils (93) and activates platelets (94) |
|
Formyl peptide receptors (FPRs) | Trauma with SIRS (95), liver injury (53), localized juvenile periodontitis (96) |
Succinate | Intermediate synthetized in the TCA cycle or metabolite of cellular respiration | Pro-inflammatory response; triggers intracellular calcium mobilization, migration and has synergistic effect with TLRs ligands for proinflammatory cytokines production in dendritic cells (97); enhances antigen-specific activation of helper T lymphocytes; enhances IL-1β production in lipopolysaccharide-primed macrophages (98) | Unclear | GPR91 (97) | Pulmonary artery hypertension (99, 100) |
Cardiolipin | Maintaining membrane potential and architecture and provides structural and functional support to protein involved in mitochondrial biogenesis | Pro-inflammatory response; activates inflammasome NLRP3 mediated immune response (101); activation and proliferation of gamma/delta T cells (102) | CD1d (102); NLRP3 (101), Atp8b1 (103) | Pneumonia (103), COPD (104) | |
Cytochrome-c | electron carrier in mitochondrial respiratory chain | Pro-inflammatory; cellular toxicity; induced lymphocytes (105) and neuronal cells (106) apoptosis |
|
Apaf-1 (108) | Myocardial infarction (109), liver diseases (110, 111), cancer (112, 113), SIRS/MODS (114), acute encephalopathy (115), hemodialysis (116) |
mtDNA, mitochondrial DNA; NET, neutrophil extracellular trap; TLR9, toll-like receptor 9; NLRP3, NOD, LRR and pyrin domain-containing protein 3; AIM2, absent in melanoma 2; NLRC4, NLR family CARD domain containing 4; STING, stimulator of interferon genes; SLE, systemic lupus erythematosus; CFTR, cystic fibrosis transmembrane conductance regulator; ATP, adenosine triphosphate; TFAM, mitochondrial transcription factor A; COPD, chronic obstructive pulmonary disease; SIRS, systemic inflammatory response syndrome; MODS, multiple organ dysfunction syndrome; Apaf-1, apoptotic protease activating factor-1.