Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa

Abstract

Although studies in rat cultured pulmonary artery endothelial cells, perfused lungs, and intact mice support the concept that oxidative mitochondrial (mt) DNA damage triggers acute lung injury (ALI), it has not yet been determined whether enhanced mtDNA repair forestalls development of ALI and its progression to multiple organ system failure (MOSF). Accordingly, here we examined the effect of a fusion protein construct targeting the DNA glycosylase, Ogg1, to mitochondria in a rat model intra-tracheal P. aeruginosa (strain 103; PA103)-induced ALI and MOSF. Relative to controls, animals given PA103 displayed increases in lung vascular filtration coefficient accompanied by transient lung tissue oxidative mtDNA damage and variable changes in mtDNA copy number without evidence of nuclear DNA damage. The approximate 40% of animals surviving 24h after bacterial administration exhibited multiple organ dysfunction, manifest as increased serum and tissue-specific indices of kidney and liver failure, along with depressed heart rate and blood pressure. While administration of mt-targeted Ogg1 to control animals was innocuous, the active fusion protein, but not a DNA repair-deficient mutant, prevented bacteria-induced increases in lung tissue oxidative mtDNA damage, failed to alter mtDNA copy number, and attenuated lung endothelial barrier degradation. These changes were associated with suppression of liver, kidney, and cardiovascular dysfunction and with decreased 24h mortality. Collectively, the present findings indicate that oxidative mtDNA damage in lung tissue initiates PA103-induced ALI and MOSF in rats.

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

“…Consistent with these data, mice overexpressing SIRT3 have sustained expression of OGG1, preserved mtDNA integrity and are protected from bleomycin-induced lung fibrosis 203 . As a therapeutic approach, mitochondria-targeted OGG1 has been shown to limit oxidant-induced mtDNA damage and lung injury 205,206 . SIRT3 is also regulated by levels of NAD.…”

Enhanced Mitochondrial DNA Repair Resuscitates Transplantable Lungs Donated After Circulatory Death

“…[27][28][29][30][31][32][33] Pharmacologic enhancement of mtDNA repair also suppresses the release of proinflammatory mtDNA DAMPs and propagation of mtDNA damage culminating in activation of toll-like receptor 9 to initiate a regenerative cycle of mtDNA damage and DAMP release culminating in acute respiratory distress syndrome and multiple organ system failure. 12,38 We examined the postulated sentinel function of mtDNA damage in the context of physiological degradation of lungs produced after DCD, reasoning that this particular mode of lung donation could benefit from a targeted pharmacologic strategy to improve organ quality. Evidence supporting involvement of mtDNA damage in lung physiological degradation after DCD obtained in the present study is the association between physiological abnormalities, oxidative base damage in the mitochondrial genome, and accumulation of mtDNA fragments in lung perfusate.…”

“…The failure of the fusion protein to diminish perfusate nuclear DNA fragments originating from the 28S RNA nuclear sequence attests to the specificity of the repair protein construct for the mitochondrial genome, which has been reported previously. 25,38 Additional evidence that oxidative mtDNA damage triggered lung endothelial barrier dysfunction after DCD is derived from the finding that mutant OGG1, devoid of DNA glycosylase activity, failed to suppress changes in barrier function, mtDNA damage or mtDNA DAMP accumulation in perfusate.…”

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

“…Mitochondrial dysfunction leads to an increase in ROS production, mitochondrial DNA damage (copy number reduction and mutation), disorders in oxidative phosphorylation of the mitochondrial respiratory chain, and the reduction of ATP production [33]. Mitochondrial dysfunction is closely associated with lung injury [15, 16]. Regulation of mitochondrial dysfunction attenuates lung tissue damage [13, 14].…”

“…Moreover, mitochondrial DNA provokes systemic inflammation in lipopolysaccharide (LPS)-induced lung injury in rats [15]. Furthermore, mitochondrial DNA damage initiates lung injury and multi-organ system failure in rats following intra-tracheal Pseudomonas aeruginosa administration [16]. In addition, mitochondrial ROS are considered to be important factors in NOD-like receptor protein-3 (NLRP3) inflammasome activation [12].…”