Role of released mitochondrial DNA in acute lung injury

Abstract

Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) is a form of acute-onset hypoxemic respiratory failure characterised by an acute, diffuse, inflammatory lung injury, and increased alveolar-capillary permeability, which is caused by a variety of pulmonary or nonpulmonary insults. Recently, aberrant mitochondria and mitochondrial DNA(mtDNA) level are associated with the development of ALI/ARDS, and plasma mtDNA level shows the potential to be a promising biomarker for clinical diagnosis and evaluation of lung injury severity. In mechanism, the mtDNA and its oxidised form, which are released from impaired mitochondria, play a crucial role in the inflammatory response and histopathological changes in the lung. In this review, we discuss mitochondrial outer membrane permeabilisation (MOMP), mitochondrial permeability transition pore(mPTP), extracellular vesicles (EVs), extracellular traps (ETs), and passive release as the principal mechanisms for the release of mitochondrial DNA into the cytoplasm and extracellular compartments respectively. Further, we explain how the released mtDNA and its oxidised form can induce inflammatory cytokine production and aggravate lung injury through the Toll-like receptor 9(TLR9) signalling, cytosolic cGAS-stimulator of interferon genes (STING) signalling (cGAS-STING) pathway, and inflammasomes activation. Additionally, we propose targeting mtDNA-mediated inflammatory pathways as a novel therapeutic approach for treating ALI/ARDS.

Mitochondria-derived vesicles and their potential roles in kidney stone disease

“…Many lines of MDVs research have shown greater MDVs level in mild stress conditions than mitophagy, which is the canonical machinery for removing the damaged mitochondria [ 1 , 8 – 11 ]. Recently, selective cargos of mitochondrial oxidized molecules, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be degraded by lysosomes have been shown [ 3 , 12 , 13 ]. Moreover, immune regulation by MDVs has been emphasized in several reports of inflammation-associated diseases [ 3 , 12 , 14 ].…”

“…Recently, selective cargos of mitochondrial oxidized molecules, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be degraded by lysosomes have been shown [ 3 , 12 , 13 ]. Moreover, immune regulation by MDVs has been emphasized in several reports of inflammation-associated diseases [ 3 , 12 , 14 ]. As such, MDVs have gained a wide interest in many mitochondria-associated disorders/diseases, such as cancers [ 15 , 16 ], aging [ 17 – 19 ], cardiovascular diseases [ 20 , 21 ], and neurodegenerative disorders [ 22 – 24 ].…”

IL-37 ameliorates myocardial fibrosis by regulating mtDNA-enriched vesicle release in diabetic cardiomyopathy mice

“…Previous studies have demonstrated that mtDNA can trigger inflammatory cytokine production and aggravate lung fibrosis through TLR9 signaling and noncanonical cGAS-STING signaling [51]. In thoracic transverse aortic constriction induced cardiomyopathy, mtDNA is capable of inducing dilated cardiomyopathy through TLR9 signaling [22].…”

Peak Plasma Levels of mtDNA Serve as a Predictive Biomarker for COVID-19 in-Hospital Mortality

“…In contrast, the release of mtDNA during COVID-19 has been investigated significantly less, even though it is related to NETs and immunothrombosis. Therefore, the present study aimed to quantify mtDNA [ 38 , 39 , 40 ].…”