Mitochondrial Dysfunction Increases Allergic Airway Inflammation

Abstract

The prevalence of allergies and asthma among the world’s population has been steadily increasing due to environmental factors. It has been described that exposure to ozone, diesel exhaust particles, or tobacco smoke exacerbates allergic inflammation in the lungs. These environmental oxidants increase the levels of cellular reactive oxygen species (ROS) and induce mitochondrial dysfunction in the airway epithelium. In this study, we investigated the involvement of preexisting mitochondrial dysfunction in the exacerbation of allergic airway inflammation. After cellular oxidative insult induced by ragweed pollen extract (RWE) exposure, we have identified nine oxidatively damaged mitochondrial respiratory chain-complex and associated proteins. Out of these, the ubiquinol-cytochrome c reductase core II protein (UQCRC2) was found to be implicated in mitochondrial ROS generation from respiratory complex III. Mitochondrial dysfunction induced by deficiency of UQCRC2 in airway epithelium of sensitized BALB/c mice prior the RWE challenge increased the Ag-induced accumulation of eosinophils, mucin levels in the airways, and bronchial hyperresponsiveness. Deficiency of UQCRC1, another oxidative damage-sensitive complex III protein, did not significantly alter cellular ROS levels or the intensity of RWE-induced airway inflammation. These observations suggest that preexisting mitochondrial dysfunction induced by oxidant environmental pollutants is responsible for the severe symptoms in allergic airway inflammation. These data also imply that mitochondrial defects could be risk factors and may be responsible for severe allergic disorders in atopic individuals.

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

“…This compound can then reach the cytoplasm after opening of the mitochondrial transition pore (refs. 69-71); thereby, hydrogen peroxide generated in mitochondria acts as a signaling mediator that induces NF-κB activation (12,72). Our data are in support of these studies, as we found that epithelial Mt-CaMKIIN expression reduced stimulant-mediated oxidative stress and altered mitochondrial function (measured by Mt-ROS and OCR), which correlated with reduced NF-κB activation.…”

“…in asthma; however, sources of these phenomena are unclear (6,7,(10)(11)(12)54). One potential clue is that mitochondrial CaMKII inhibition is protective in a variety of myocardial injury models linked to elevated ROS and mitochondrial dysfunction (7,20,55,56).…”

Antioxidant Strategies in the Treatment of Bronchial Asthma

“…The mitochondrial form of SOD (MnSOD or SOD2) is oxidatively inactivated in asthmatic airway samples 4 , suggesting that impairment of mitochondrial oxidative defenses might contribute to the asthmatic phenotype. Evidence for mitochondrial injury in murine asthma models 2,3 , discussed earlier, is consistent with this hypothesis, though the mechanism(s) of mitochondrial damage have not been elucidated. SOD2 polymorphisms are also associated with bronchial hyperresponsivenss in humans 83 .…”

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

“…To mimic oxidative stress conditions we treated the cells with antimycin A, which binds to cytochrome b and inhibits electron flow from semiquinone to ubiquinone, consequently increasing the steady state concentration of semiquinone and resulting in electron escape from complex III [43,44]. This impairment of the electron transport system can increase mitochondrial ROS generation leading to oxidative damage of mtDNA [45].…”