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. 2018 May 4;9:832. doi: 10.3389/fimmu.2018.00832

Table 1.

Mitochondrial damage-associated molecular patterns.

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
  • (a)

    Passive release (via necrosis, necroptosis (17, 18), apoptosis)

  • (b)

    Active release [via mitochondria derived vesicles (1922)]

TLR9, inflammasomes [NLRP3, AIM2 and NLRC4 (2325)], STING (2628) Sepsis (2937), trauma (31, 36, 3843), cardiogenic shock (30, 44), cancer (4552), liver failure (53, 54), heart failure (55), atherosclerosis (56), strokes (57), rheumatoid arthritis (58, 59), SLE (6062)
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)
  • (a)

    Passive release by necrotic cells

  • (b)

    Active secretion by vascular cells via vesicular exocytosis, and pannexin channel (77)

  • (c)

    Active secretion by epithelial cells via CFTR dependent (78) or independent mechanism (79)

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)
  • (a)

    Passive release via necrotic cells

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)
  • (a)

    Passive release via necrotic cells

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
  • (a)

    Passive release via necrosis or apoptosis (107)

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.