Mitochondrial biology in airway pathogenesis and the role of NRF2

Abstract

A constant improvement in understanding of mitochondrial biology has provided new insights into mitochondrial dysfunction in human disease pathogenesis. Impaired mitochondrial dynamics caused by various stressors are characterized by structural abnormalities and leakage, compromised turnover, reactive oxygen species overproduction in mitochondria as well as increased mitochondrial DNA mutation frequency, which leads to impaired energy production and modified mitochondria-derived cell signaling. The mitochondrial dysfunction in airway epithelial, smooth muscle, and endothelial cells has been implicated in diseases including chronic obstructive lung diseases and acute lung injury. Increasing evidence indicates that the NRF2-antioxidant response element (ARE) pathway not only enhances redox defense but also facilitates mitochondrial homeostasis and bioenergetics. Identification of functional or potential AREs further supports the role for Nrf2 in mitochondrial dysfunction-associated airway disorders. While clinical reports indicate mixed efficacy, NRF2 agonists acting on respiratory mitochondrial dynamics are potentially beneficial. In lung cancer, growth advantage provided by sustained NRF2 activation is suggested to be through increased cellular antioxidant defense as well as mitochondria reinforcement and metabolic reprogramming to the preferred pathways to meet the increased energy demands of uncontrolled cell proliferation. Further studies are warranted to better understand NRF2 regulation of mitochondrial functions as therapeutic targets in airway disorders.

Effects of Hyperoxia on Mitochondrial Homeostasis: Are Mitochondria the Hub for Bronchopulmonary Dysplasia?

“…The expression of NOX2 and NOX4 in vascular endothelial cells increases under hyperoxia (Pendyala et al, 2009) and can activate two antioxidant response elements (ARE) on the NOX4 promoter in pulmonary vascular endothelial cells. Loss or mutation of nuclear factor erythroid 2-related factor 2 (Nrf2) can cause mitochondrial dysfunction and metabolic disorders induced by ROS (Cho and Kleeberger, 2020). The transcription level of NOX4 can also promote angiogenesis and migration through Nrf2-ARE (Pendyala et al, 2011).…”

Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS

“…Mitochondrial dysfunction and its potential mechanistic role in the pathophysiology of lung diseases such as COPD, asthma, pulmonary arterial hypertension, or idiopathic pulmonary fibrosis is increasingly recognised (9)(10)(11). Clinical observational data suggest that mitochondrial dysfunction has been associated with higher mortality in critically ill patients with sepsis (12) and survivors of the Multiple Organ Dysfunction Syndrome had better mitochondrial function with preservation of ATP and biogenesis markers (13).…”

Sirtuin 3 Inhibits Airway Epithelial Mitochondrial Oxidative Stress in Cigarette Smoke-Induced COPD

“…Thus, the impairment of airway epithelial cell function may initiate the pathogenesis of COPD [ 25 ]. It is well known that mitochondrial dysfunction leads to airway epithelial cell damage [ 26 ], thus airway epithelial mitochondrial damage is involved in the pathogenesis of COPD. Structural and functional changes of the mitochondria in the epithelium of COPD lungs are potentially the consequence of long-term exposure to cigarette smoke [ 27 ].…”