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. Author manuscript; available in PMC: 2024 Jun 20.
Published in final edited form as: Annu Rev Biochem. 2023 Mar 31;92:299–332. doi: 10.1146/annurev-biochem-032620-104401

Table 1.

Inflammatory pathology associated with mtDNA release

Category Disease mtDNA-driven inflammatory signaling
Age-related diseases Age-related hearing loss ■ Increased cytosolic mtDNA, cGAS–STING signaling, and cytokines in the cochlea, inferior colliculus, and auditory cortex of aged C57BL/6J male mice (187).
Age-related macular degeneration ■ Release of mtDNA leading to activation of cGAS, mitochondrial damage, and mPTP activation, promoting the activity of NLRP3 inflammasomes (106).
Autoimmunity Periodic fever syndromes ■ Defective autophagy prevents clearance of damaged mitochondria, causing mtROS and mtDNA–NLRP3 inflammasome signaling and hypersecretion of IL-1β and IL-18 in monocytes (207).
Rheumatoid and inflammatory arthritis ■ Ox-mtDNA in the synovial fluid of patients (199).
■ Injection of mtDNA into joints induces arthritis via NF-κB signaling and recruitment of monocytes and macrophages (33).
Systemic lupus erythematosus ■ Ox-mtDNA is a component of NETs and triggers type I IFN when released (5052).
■ IFNα impairs autophagy and leads to an accumulation of dysfunctional mitochondria and cytosolic mtDNA, which drives cGAS–STING signaling (208).
■ Impaired mitophagy in red blood cells prevents the clearance of mitochondria. When these red blood cells are internalized by macrophages, mtDNA is released and drives cGAS–STING signaling (154).
■ Inhibiting VDAC oligomerization ameliorates mtDNA release and lupus-like symptoms in an SLE mouse model (31).
Systemic sclerosis ■ Patients with ATAD3A mutations display increased type I IFN signaling associated with systemic sclerosis and other symptoms, including neurological. Patient cells display increased ISG expression dependent upon cGAS, STING, and mtDNA, which can be partially reversed by VDAC inhibition (DIDS) or rapamycin treatment (76).
Bacterial infection Escherichia coli O157:H7 ■ Mitochondrial damage leading to mtDNA release and NLRP3 inflammasome activation (170).
Mycobacterium tuberculosis ■ Infection by some strains induces mitochondrial stress and ROS, mtDNA release, and cGAS–STING signaling (172).
Mycobacterium abscessus ■ Infection induces mtROS, release of ox-mtDNA, cGAS–STING signaling and NLRP3 inflammasome signaling. mtROS damages phagosomes, enabling bacterial escape and replication (174).
Pseudomonas aeruginosa ■ Infection causes oxidative damage and release of mtDNA fragments from lung cells (209).
■ mtDNA–cGAS signaling activates autophagy, promoting clearance of bacteria as well as damaged mitochondria. Enhanced mtDNA release improves cellular response to infection, and cGAS deficiency impairs bacterial clearance and leads to heightened mtDNA-driven TLR9 and NLRP3/NLRC4 inflammasome responses (167169).
Salmonella Typhimurium ■ Release of mtDNA and mtDNA–cGAS–STING signaling inhibits bacterial replication (171).
Streptococcus pneumoniae ■ Sepsis induces mtROS, mtDNA damage and release, and activation of TLR9 in heart tissue (210).
Blood disorders Sickle cell anemia ■ Sickle red blood cells retain mitochondria, leading to an increase in circulating mtDNA, which then triggers increased NET formation dependent upon TBK1 (211).
Cancer Chemotherapeutic resistance ■ Chronic mtDNA stress causes upregulation of a specific subset of ISGs (IRDs) via the U-ISGF3 complex, promoting enhanced nuclear DNA repair. The chemotherapeutic drug doxorubicin causes mtDNA damage and release, and mtDNA release and signaling in melanoma cells promotes resistance to doxorubicin in vivo (212).
Cardiovascular disease Atherosclerosis ■ Release of ox-mtDNA and activation of the NLRP3 inflammasome, leading to increased atherosclerotic plaques (110).
■ mtDNA that escapes autophagy activates TLR9 and drives aortic inflammation and atherosclerosis in LDL receptor knockout mice (213).
■ LL-37-bound mtDNA escapes autophagy, accumulates in atherosclerotic plaques, and activates TLR9, causing immune cell activation, recruitment, and autoimmune responses (145).
■ Loss of DNMT3A or TET2 activity in human monocyte-derived macrophages and atherosclerotic macrophages causes downregulation of TFAM, triggering mtDNA stress and release and cGAS–STING signaling (214).
Cardiomyopathy ■ mtDNA that is not degraded by autophagy, due to depletion of DNase II, drives TLR9 signaling, leading to heart failure (43).
■ Increased cGAS–STING signaling in diabetic cardiomyopathy, partial reversal of pathology with STING inhibition. Palmitic acid treatment of H9C2 cells increases ROS and mtDNA release, suggesting that lipotoxicity drives mtDNA–cGAS–STING signaling (93, 94).
■ Several lines of evidence implicate increased circulating mtDNA and TLR9 signaling in acute myocardial infarction (215).
Friedreich ataxia ■ Acute knockdown of frataxin in iPSC-derived cardiomyocytes induces mitochondrial dysfunction, mtDNA release, cGAS activation, and a type I IFN response, implicating mtDNA-driven inflammation in cardiomyopathy associated with this disease (216).
Hypertension ■ Increased circulating mtDNA in hypertensive rats, associated with diminished DNase activity and TLR9 signaling. TLR9 inhibition reduced blood pressure in hypertensive rats, whereas administering a TLR9 agonist to healthy rats increased systolic blood pressure (217).
Chronic inflammatory diseases Kawasaki disease ■ Increased circulating mtDNA and expression of CD36 and AIM2 (218).
Idiopathic pulmonary fibrosis ■ Increased mtDNA–cGAS–STING signaling driving senescence in alveolar epithelial cells (195, 196).
Inflammatory bowel disease ■ Increased circulating mtDNA and TLR9 signaling associated with mitochondrial damage (219).
Dental disease Pulpitis ■ BAX-mediated mtDNA release occurs during gasdermin-D-driven pyroptosis, activating STING-driven inflammation in odontoblasts (28).
Liver diseases Acute liver injury ■ Increased levels of circulating mtDNA in response to liver injury with inflammation dependent upon TLR9 (220).
Hepatocellular carcinoma ■ Hypoxia increases mtROS and mtDNA release; released mtDNA binds HMGB1 and activates TLR9 signaling, which promotes tumor growth (144).
NASH, NAFLD, and liver fibrosis ■ In the context of HFD-induced NASH, ox-mtDNA is released into plasma and present within microparticles, which activate TLR9. Blocking TLR9 signaling pharmacologically prevents the development of NASH (221).
■ Increased circulating mtDNA associated with fibrosis, NAFLD, and NASH (222).
Metabolic disease Obesity ■ mtDNA release and cGAS–STING signaling in the adipose tissue of HFD-fed mice. Loss of DsbA-L, a chaperone in the matrix, causes mtDNA release and cGAS–STING signaling, leading to decreased thermogenesis and energy expenditure, thereby promoting obesity. Overexpression of DsbA-L protects against HFD-induced obesity (95, 96).
■ Release of mtDNA into the cytoplasm of pancreatic beta cells accelerates senescence, causing glucose intolerance and insulin resistance in aged, HFD-fed mice, and these effects are improved by STING inhibition (92).
Type II diabetes ■ Increased circulating mtDNA, leading to AIM2 inflammasome activity and secretion of IL-1β and IL-18 (223).
Neurodegenerative disease Amyloid lateral sclerosis ■ Disease mutations in TDP-43 cause its localization to mitochondria, where it triggers mtDNA release and cGAS–STING signaling dependent upon VDAC and mPTP but not BAK/BAX. Deletion of STING in a TDP-43 overexpression mouse model of ALS slows neurodegeneration and extends life span (224).
Huntington’s disease ■ Increased mtDNA release that correlates with disease progression and is associated with ox-mtDNA in synaptic mitochondria. Increased cGAS–STING signaling associated with cytokine production and synaptic degeneration.
■ Melatonin administration reduces mtDNA release and cGAS–STING signaling in mouse models of HD.
■ Melatonin deficiency is associated with increased mtROS, mtDNA damage, and permeability transition, causing mtDNA–cGAS–STING signaling, and is associated with accelerated aging (185).
Parkinson’s disease ■ mtDNA mutational stress increases circulating mtDNA and cytokines and causes dopaminergic neurodegeneration in a STING-dependent fashion in Parkin−/− and mutator mice (5).
■ Escape of mtDNA from lysosomes, causing cell death in cultured cells and zebrafish models of PD (6).
■ Loss of VPS13C/PARK23, which is mutated in PD, causes lysosomal dysfunction leading to mtDNA leakage into the cytosol, cGAS–STING signaling, and impaired STING degradation, which perpetuates signaling (4).
■ Deficiency of LRRK2, also mutated in PD, leads to increased mitochondrial stress and mtDNA–cGAS–STING signaling. Lrrk−/− mice display higher inflammatory responses when infected with M. tuberculosis (7). The disease mutation Lrrk2G2019S causes mitochondrial dysfunction, causing enhanced AIM2 inflammasome activation in macrophages infected by M. tuberculosis. Enhanced mtROS production drives the association of gasdermin D with mitochondria, exacerbating mitochondrial DAMP release and promoting cell death via necroptosis as opposed to pyroptosis (173).
Trauma and injury Acute lung injury and acute respiratory distress syndrome ■ Increased levels of circulating mtDNA that correlate with disease severity, along with increased levels of mtDNA present in the bronchoalveolar lavage fluid and heightened TLR9, cGAS–STING, and NLRP3 inflammasome signaling (225).
Acute kidney injury ■ Cisplatin induces cGAS–STING signaling during acute kidney injury; cultured cells treated with cisplatin release mtDNA in a BAX-dependent manner (27).
■ mtDNA is released into circulation during septic acute kidney injury and activates TLR9 signaling, causing renal dysfunction (226).
■ Increased IL-18, suggesting that circulating mtDNA may also drive inflammasome activation (227).
■ Increased circulating mtDNA and TFAM arising from acute kidney injury drive inflammation and mitochondrial dysfunction in secondary lung injury (228).
Burn trauma ■ Release of mtDNA into circulation and cGAS–STING signaling in unaffected tissue, secondary acute lung injury associated with activated neutrophils (229).
Sepsis ■ Increased circulating mtDNA, and higher levels correlate with increased mortality (230).
SIRS ■ mtDNA is released into circulation and activates TLR9, leading to cytokine production and neutrophil activation (48, 49).
■ Increased circulating mtDNA after severe injury, and higher levels correlate with SIRS, MODS, and mortality (230, 231).
Viral infection Many viruses ■ The following cause mtDNA release during infection: HSV-1 and HSV-2 (65), IAV (157, 119), ECMV (157), DENV (158, 159), ZIKV (161), MeV (162), SARS-CoV-2 (164), KSHV (232), SFTSV (120), PRRSV (160).

Abbreviations: ALS, amyloid lateral sclerosis; cGAS, cGMP–AMP synthase; DAMP, damage-associated molecular pattern; DENV, dengue virus; DIDS, 4,4’-Diisothiocyanatostilbene-2,2’-disulfonate; ECMV, encephalomyocarditis virus; HD, Huntington’s disease; HFD, high-fat diet; HSV, herpes simplex virus; IAV, influenza A virus; IFN, interferon; IL, interleukin; ISG, interferon-stimulated gene; iPSC, induced pluripotent stem cells; KSHV, Kaposi’s sarcoma- associated herpesvirus; LDL, low-density lipoprotein; MeV, measles virus; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; MODS, multiple organ dysfunction syndrome; NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; NET, neutrophil extracellular traps; NF-κB; nuclear factor κB; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; ox-mtDNA, oxidized mtDNA; PD, Parkinson’s disease; PRRSV, porcine reproductive and respiratory syndrome virus; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SFTSV, severe fever with thrombocytopenia syndrome virus; SIRS, systemic inflammatory response syndrome; SLE, systemic lupus erythematosus; TBK1, TANK-binding kinase 1; TFAM, transcription factor A mitochondrial; TLR, Toll-like receptor; VDAC, voltage-dependent anion channel; ZIKV, Zika virus.