Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive and disabling disorder marked by airflow limitation and extensive destruction of lung parenchyma. Cigarette smoke is the major risk factor for COPD development and has been associated with increased oxidant burden on multiple cell types in the lungs. Elevated levels of reactive oxygen species (ROS) may significantly affect expression of biological molecules, signaling pathways, and function of antioxidant defenses. Although inflammatory cells, such as neutrophils and macrophages, contribute to the release of large quantities of ROS, mitochondrial dysfunction plays a critical role in ROS production due to oxidative phosphorylation. Although mitochondria are dynamic organelles, excess oxidative stress is able to alter mitochondrial function, morphology, and RNA and protein content. Indeed, mitochondria may change their shape by undergoing fusion (regulated by mitofusin 1, mitofusin 2, and optic atrophy 1 proteins) and fission (regulated by dynamin-related protein 1), which are essential processes to maintain a healthy and functional mitochondrial network. Cigarette smoke can induce mitochondrial hyperfusion, thus reducing mitochondrial quality control and cellular stress resistance. Furthermore, diminished levels of enzymes involved in the mitophagy process, such as Parkin (a ubiquitin ligase E3) and the PTEN-induced putative kinase 1 (PINK1), are commonly observed in COPD and correlate directly with faulty removal of dysfunctional mitochondria and consequent cell senescence in this disorder. In this review, we highlight the main mechanisms for the regulation of mitochondrial quality and how they are affected by oxidative stress during COPD development and progression.

Highlights

  • Chronic obstructive pulmonary disease (COPD) is a slowly progressive pulmonary disorder that affects over 300 million people worldwide

  • Neutrophil myeloperoxidase catalyzes the oxidation reaction of chloride ions (Cl−) by hydrogen peroxide to generate the anionic reactive oxygen species (ROS) hypochlorite or hypochlorous acid (HClO); in turn, HClO reacts with low-molecular-weight amines to produce chloramines, which lead to cellular protein damage [28]

  • We have provided an overview of some key endogenous sources of oxidative burden and their role in COPD pathogenesis

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Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a slowly progressive pulmonary disorder that affects over 300 million people worldwide. Mitochondrial ROS may be derived from up to 12 potential sites associated with nutrient oxidation and the electron transport chain (ETC), divided into two subgroups: the reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide (NADH/NAD+) isopotential group and the ubiquinol/reduced ubiquinone (UQH2/UQ) isopotential group. These different sites make variable contributions to the overall release of O2−/H2O2 depending on cell type and tissue, which seems to be related to substrate availability and mitochondrial bioenergetics (Table 1) [9, 10]. High concentrations of O2− play a key role in excess ROS production

Neutrophil-Derived ROS in COPD
Oxidative Mitochondrial Dysfunction in COPD
Antioxidant Defenses in COPD
Conclusion
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