Differential regulation of autophagy and mitophagy in pulmonary diseases

Abstract

Lysosomal-mediated degradation of intracellular lipids, proteins and organelles, known as autophagy, represents a inducible adaptive response to lung injury resulting from exposure to insults, such as hypoxia, microbes, inflammation, ischemia-reperfusion, pharmaceuticals (e.g., bleomycin), or inhaled xenobiotics (i.e., air pollution, cigarette smoke). This process clears damaged or toxic cellular constituents and facilitates cell survival in stressful environments. Autophagic degradation of dysfunctional or damaged mitochondria is termed mitophagy. Enhanced mitophagy is usually an early response to promote survival. However, overwhelming or prolonged mitochondrial damage can induce excessive/pathological levels of mitophagy, thereby promoting cell death and tissue injury. Autophagy/mitophagy is therefore an important modulator in human pulmonary diseases and a potential therapeutic target. This review article will summarize the most recent studies highlighting the role of autophagy/mitophagy and its molecular pathways involved in stress response in pulmonary pathologies.

Keywords: ALI; COPD; IPF; PAH; PH.

Fig. 1.

Autophagy and mitophagy regulation. mTOR is inhibited by starvation, allowing ULK1/FIP200 activation and initiation of autophagosomal formation, as well as TFEB activation allowing further increase of transcription of autophagy and lysosome genes. Rapamycin and Torin1 are inhibitors of mTOR and activators of autophagy. Furthermore, two ubiquitin-like conjugation systems are regulated by ATG7-ATG10 and ATG4-ATG7-ATG3, resulting in ATG5-ATG12-ATG16 complex and cytosolic LC3-I lipidation to form LC3-II, which inserts into autophagosome membranes. SQSTM1/p62 has a ubiquitin binding domain and an LC3 interacting domain and thus is capable of bringing ubiquitinated cargos to the autophagosomes. Upon fusion with lysosomes, the autophagosome cargos, together with LC3-II in the inner membrane and p62, are degraded. Chloroquine, bafilomycin, pepstatin A, and E64 inhibit lysosomal function and inhibit autophagic flux. Beclin-VPS34 complex also play an activating role in autophagy and is inhibited by 3-MA. PINK1 and PARKIN localization to the mitochondria are involved in mitophagy. Carbamazepine and trehalose have also been found to stimulate autophagy, although the exact mechanism of their action is unclear.

Fig. 2.

Acute lung injury and autophagy. Autophagy may play a protective or a detrimental role in acute lung injury, as the blue shaded boxes summarize examples of inhibition of autophagy by genetic or pharmacological approaches exacerbated injury. Brown shaded boxes summarize examples that activation of autophagy decreased lung injury, and converse examples of inhibition of autophagy by genetic or pharmacological approaches decreased lung injury.

Fig. 3.

COPD and autophagy/mitophagy. COPD may be associated with either increased LC3B-II and autophagosome numbers and increased mitophagy, or decreased mitophagy protein and decreased clearance of autophagy/mitophagy substrates. Examples that downregulation of autophagy may be detrimental are shown in the blue shaded boxes, and examples that both upregulation and downregulation of autophagy may be protective are shown in the brown shaded box.

Fig. 4.

IPF association with autophagy and mitophagy. Examples that downregulation of autophagy may be detrimental are shown in the blue shaded boxes, and examples that up- or downregulation of autophagy may be protective are shown in the brown shaded box.

Fig. 5.

PH association with autophagy and mitophagy. Examples that autophagy may play a protective role are shown in the blue shaded boxes, and examples that autophagy may be detrimental are shown in the brown shaded box.