Cigarette
smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in
chronic obstructive pulmonary disease (
COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative
protein kinase 1)-PRKN (parkin RBR E3
ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in
COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in
COPD progression. To clarify the involvement of PRKN-regulated mitophagy in
COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1
protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN
protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in
COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of
COPD. Abbreviations: AD:
Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT
serine/threonine kinase; CALCOCO2/NDP52:
calcium binding and coiled-coil domain 2; CDKN1A:
cyclin dependent kinase inhibitor 1A; CDKN2A:
cyclin dependent kinase inhibitor 2A;
COPD:
chronic obstructive pulmonary disease; CS: cigarette
smoke; CSE: CS extract; CXCL1: C-X-C motif
chemokine ligand 1; CXCL8: C-X-C motif
chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL:
interleukin; KO: knockout; LF: lung fibroblasts; LPS:
lipopolysaccharide; MAP1LC3/LC3:
microtubule associated protein 1 light chain 3; MTOR: mechanistic target of
rapamycin kinase; 8-OHdG:
8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3
ubiquitin protein ligase; PCD: programmed cell death; PFD:
pirfenidone; PIK3C:
phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1:
PTEN induced putative kinase 1;
PTEN: phosphatase and
tensin homolog; RA:
rheumatoid arthritis; ROS:
reactive oxygen species; SA-GLB1/β-Gal: senescence-associated-
galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF:
tumor necrosis factor.