Table 1.

Role of mtDNA as inflammatory molecules in human pathologies described in this review.

Pathology		Observation/Mechanism	Type of Study/Sample	Reference
Trauma	Systemic inflammatory response syndrome (SIRS)	mtDNA plasma levels were significantly higher in trauma patients, and a correlation between mtDNA levels and clinical severity was observed	Blood from patients with SIRS	[148,149]
	Multiple organic dysfunction syndrome (MODS)	mtDNA concentrations were predictive for the development of MODS (in patients) or organ dysfunction (in an animal model)	Plasma from severely injured patients	[150] [149]
	Traumatic injury and shock	Release of mtDNA triggers the development of severe tissue injury	Plasma from an animal model of trauma	[150]
	Trauma	TLR9-mediated NETs formation triggered by mtDNA	Plasma from trauma patients	[94]
	Trauma and sepsis	An increase in mtDNA plasma levels was observed, although differences in disease course and prognostic were observed, suggesting that the mechanism of release of mtDNA is different between the two groups	Blood from patients presenting trauma or severe sepsis	[151]
	Trauma and haemorrhagic shock	mtDNA release triggers the activation of neutrophils	Rat model of trauma and haemorrhagic shock	[34]
Autoimmune origin	Multiple sclerosis (MS)	mtDNA level, together with other pro-inflammatory cytokines, was observed to be higher in patients with progressive forms of MS, which probably contributes to the systemic inflammation present in the pathology	Plasma from MS patients	[84]
		Increased levels of cf-mtDNA in patients with relapsing-remitting form of MS An inverse correlation was observed between cf-mtDNA and disease duration	CSF from MS patients	[165]
	Lupus-like disease	VDAC-mediated mtDNA release	In vitro and in vivo animal model of SLE	[74]
		Neutrophil-mediated ox-mtDNA release	Blood from SLE patients	[101]
		NETosis inductors triggered the release of ox-mtDNA, leading to STING activation	Blood from patients with CGD or SLE In vitro models Iv vivo animal model of CGD or SLE	[91]
Cancer	Advanced epithelial ovarian cancer (EOC)	The levels of mtDNA ascites were correlated with worse outcome in EOC patients	Blood from EOC patients	[155]
	Hormonal therapy-resistant breast cancer	mtDNA release via exosomes	Blood from patients with breast cancer In vitro and in vivo animal cancer models	[128]
	Myelodysplastic syndromes (MDS)	Ox-mtDNA release after inflammasome activation	Blood from patients with MDS In vitro cancer model	[49]
Other	Sickle cell disease	Increased circulating levels of cf-mtDNA Activation of NETs formation and cGAS-STING pathway triggered by elevated levels of cf-mtDNA The results showed a mitochondrial retention by circulating SCD red blood cells, therefore the authors suggested that this could be the source of the elevated levels of cf-mtDNA	Blood from SCD patients	[99]
	Non-alcoholic steatohepatitis	mtDNA activation of TLR9	Blood from patients with non-alcohol steatohepatitis In vivo models of NASH	[38]
	Macular degeneration	cGAS activation by mtDNA, released into cytosol by Alu-RNA accumulation	In vivo animal model of RPE degeneration	[61]