Autophagy/Mitophagy in Airway Diseases: Impact of Oxidative Stress on Epithelial Cells

Abstract

Autophagy is the key process by which the cell degrades parts of itself within the lysosomes. It maintains cell survival and homeostasis by removing molecules (particularly proteins), subcellular organelles, damaged cytoplasmic macromolecules, and by recycling the degradation products. The selective removal or degradation of mitochondria is a particular type of autophagy called mitophagy. Various forms of cellular stress (oxidative stress (OS), hypoxia, pathogen infections) affect autophagy by inducing free radicals and reactive oxygen species (ROS) formation to promote the antioxidant response. Dysfunctional mechanisms of autophagy have been found in different respiratory diseases such as chronic obstructive lung disease (COPD) and asthma, involving epithelial cells. Several existing clinically approved drugs may modulate autophagy to varying extents. However, these drugs are nonspecific and not currently utilized to manipulate autophagy in airway diseases. In this review, we provide an overview of different autophagic pathways with particular attention on the dysfunctional mechanisms of autophagy in the epithelial cells during asthma and COPD. Our aim is to further deepen and disclose the research in this direction to stimulate the develop of new and selective drugs to regulate autophagy for asthma and COPD treatment.

Keywords: COPD; asthma; autophagy; lung disease; mitophagy; oxidative stress.

Figure 1

Overview of different autophagy pathways. The panels describe the three different types of autophagy including macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy, through the formation of a double membrane vesicle surrounding the cytoplasmic cargo, forms an autophagosome which fuses with a lysosome, causing the degradation of its contents. Microautophagy induces invagination or fusion with a lysosome to degrade the cellular components. It engulfs cytoplasmic elements into autophagic tubes before fusion and degradation by lysosomal enzymes. Chaperone-mediated autophagy transports single unfolded proteins directly across the lysosomal membrane.

Figure 2

Autophagy pathway. ROS and cellular stress may inactivate mTORC1 through AMPK. Autophagy is negatively regulated by mTORC 1 inhibition that negatively regulates autophagy through direct phosphorylation of the ULK1 complex. The ULK-1 complex activates a PI3K class III complex including Beclin-1 phosphorylation and induction of VPS34 kinase activity, promoting the biogenesis of autophagosomes. The activation of the complex induces isolation membrane development, elongation, and recruitment of the Atg5–Atg12–Atg16–L1 complex that converts LC3-I to LC3-II through conjugation with phosphatidylethanolamine (PE). LC3-II binds p62 (an autophagy receptor) that links cargo proteins with the autophagosome membrane. In the final step, the autophagosome fuses with a lysosome through SNAP29 to form the autolysosome. Thus, lysosomal acid hydrolases degrade the autophagic cargo producing degradation products (such as amino acids) that are subsequently recycled back into the cytoplasm for reuse.

Figure 3

PINK1/Parkin-mediated mitophagy. (a) In healthy mitochondria, PINK1 does not accumulate on the external mitochondrial membrane; the protein is rapidly imported, processed, and degraded. (b) In damaged mitochondria following mitochondrial depolarization, PINK1 accumulates, leading to ubiquitin phosphorylation and consequent mitophagy and Parkin recruitment. Finally, activated Parkin promotes polyubiquitination which amplifies the signal for autophagy receptor recruitment and subsequent mitophagy.

Figure 4

Dysregulated autophagy/mitophagy mechanisms in COPD and asthma. Exposure to the environment/cigarette smoke/allergen induces the generation of ROS in airway epithelial cells. These cells serve as “signaling molecules” that modulate the autophagic/mitophagic cycle process through the activation of signaling molecules and pathways. Dysregulation of autophagic and mitophagic mechanisms leads to progression of chronic inflammatory lung diseases such as COPD and asthma and to the onset of airway inflammation, airway remodeling, apoptosis, airway hyper-responsiveness, increased fibrosis, mucus secretion, and senescence.