Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease

Abstract

Oxidative stress is a major hallmark of COPD, contributing to inflammatory signaling, corticosteroid resistance, DNA damage, and accelerated lung aging and cellular senescence. Evidence suggests that oxidative damage is not solely due to exogenous exposure to inhaled irritants, but also endogenous sources of oxidants in the form of reactive oxygen species (ROS). Mitochondria, the major producers of ROS, exhibit impaired structure and function in COPD, resulting in reduced oxidative capacity and excessive ROS production. Antioxidants have been shown to protect against ROS-induced oxidative damage in COPD, by reducing ROS levels, reducing inflammation, and protecting against the development of emphysema. However, currently available antioxidants are not routinely used in the management of COPD, suggesting the need for more effective antioxidant agents. In recent years, a number of mitochondria-targeted antioxidant (MTA) compounds have been developed that are capable of crossing the mitochondria lipid bilayer, offering a more targeted approach to reducing ROS at its source. In particular, MTAs have been shown to illicit greater protective effects compared to non-targeted, cellular antioxidants by further reducing apoptosis and offering greater protection against mtDNA damage, suggesting they are promising therapeutic agents for the treatment of COPD. Here, we review evidence for the therapeutic potential of MTAs as a treatment for chronic lung disease and discuss current challenges and future directions.

Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting

“…This helps explain the decreases in lung function parameters like forced expiratory volume in one second (FEV1) seen in smokers (Dailah 2022). Several therapeutic strategies targeting mechanisms disrupted by (CS) exposure have shown promise for treating major CS-induced lung diseases like COPD, pulmonary fibrosis, lung cancer, and acute respiratory distress syndrome (ARDS) (Fairley et al 2023). For COPD, metformin inhibits CS-triggered apoptosis by regulating AMP kinase, while astaxanthin suppresses CS-induced oxidative stress and inflammation by modulating Nrf2 and NF-κB pathways.…”

Mitochondrial Dysfunction in Chronic Obstructive Pulmonary Disease: Unraveling the Molecular Nexus

“…Studies utilizing advanced imaging techniques and molecular analyses in COPD patients have unequivocally confirmed the presence of mitochondrial abnormalities, establishing a direct link between genetic variations and disease manifestation. These findings underscore the clinical significance of comprehending mitochondrial genetics as a potential therapeutic target and emphasize the imperative need for further translational research to bridge the gap between laboratory discoveries and clinical applications [3,39,[43][44][45].…”

“…Investigating novel compounds, peptides, and nanoparticles with enhanced selectivity for mitochondria could yield more potent and specific interventions. Preclinical studies and early-phase clinical trials exploring the safety and efficacy of these innovative therapies are crucial for translating laboratory findings into tangible benefits for COPD patients [43].…”

Glutathione S-Transferase Genes Involved in Response to Short-Term Heat Stress in Tetranychus urticae (Koch)

“…Antioxidant enzymes play an essential role in coping with oxidative stress and regulating apoptosis and longevity. Superoxide dismutases (SOD), peroxidase (Prx), catalase (CAT), Glutathione peroxidase (GPX), and Glutathione S-transferase (GST) have been reported as the key antioxidant enzymes involved in coping with high-temperature stress in mites and insects [13]. ROS first reacts with SOD to produce H 2 O 2 and O 2 [14], and then H 2 O 2 can combine with Prx and CAT to produce H 2 O and O 2 on the one hand [15].…”