PMID- 30386443
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1880-9693 (Print)
IS  - 1880-8190 (Electronic)
IS  - 1880-8190 (Linking)
VI  - 38
DP  - 2018
TI  - PINK1-PARK2-mediated mitophagy in COPD and IPF pathogeneses.
PG  - 18
LID - 10.1186/s41232-018-0077-6 [doi]
LID - 18
AB  - Mitochondria regulate not only cell functions through energy generation but also 
      aging-associated cell phenotypes. Impaired mitochondrial structural and 
      functional integrity accompanied by excessive mitochondrial reactive oxygen 
      species (mtROS) production is associated with enhanced programmed cell death 
      (PCD) and cellular senescence. Dysregulation of mechanisms for mitochondrial 
      integrity, including mitophagy, induces accumulation of mitochondrial damage. 
      Mitophagy is a highly conserved mechanism of selectively delivering damaged 
      mitochondria for lysosomal degradation and is mainly governed by phosphatase and 
      tensin homolog (PTEN)-induced putative protein kinase 1 (PINK1) and PARK2. 
      Accumulating evidence suggests that PINK1-PARK2-mediated mitophagy has an 
      important role in the pathogenesis of aging-associated pulmonary disorders, 
      represented by chronic obstructive pulmonary disease (COPD) and idiopathic 
      pulmonary fibrosis (IPF). COPD characterized by progressive airflow limitation is 
      mainly caused by cigarette smoke (CS) exposure, and accumulation of damaged 
      mitochondria in bronchial epithelial cells (BEC) has been demonstrated. 
      Intriguingly, both enhanced and impaired mitophagy have been implicated in COPD 
      pathogenesis. Enhanced mitophagy induced by increased PINK1 expression has been 
      associated with programmed necrosis, necroptosis. On the other hand, reduced 
      PARK2 levels were linked to insufficient mitophagy, resulting in accelerated 
      cellular senescence in BEC. Although dominant involvement of PCD and cellular 
      senescence remains unclear, PINK1-PARK2-mediated mitophagy regulates 
      mitochondrial ROS and cell fate during COPD pathogenesis. Involvement of 
      insufficient mitophagy has been proposed in lung fibrosis development during IPF 
      pathogenesis. Accumulation of dysmorphic mitochondria and increased ROS 
      production linked to decrease in PINK1 expression were demonstrated in type II 
      alveolar epithelial cells (AECIIs) in IPF lungs, which can be associated with 
      enhanced apoptosis and cellular senescence. Furthermore, reduced PARK2 expression 
      levels have been shown in myofibroblasts in IPF lungs. Insufficient mitophagy 
      caused by PARK2 deficiency induced mtROS production with concomitantly activated 
      platelet-derived growth factor receptor (PDGFR)/mammalian target of rapamycin 
      (mTOR) signaling, resulting in increased myofibroblast differentiation and 
      proliferation. Inappropriate PINK1-PARK2-mediated mitophagy appears to be mainly 
      responsible for regulating cell fate, including PCD, cellular senescence, and 
      myofibroblast differentiation during COPD and IPF pathogeneses. Modalities to 
      achieve specific and appropriate levels of PINK1-PARK2-mediated mitophagy 
      activation may be a promising therapeutic option to regulate the aging-associated 
      pathology, COPD, and IPF.
FAU - Tsubouchi, Kazuya
AU  - Tsubouchi K
AD  - 1Division of Respiratory Diseases, Department of Internal Medicine, Jikei 
      University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 
      Japan. ISNI: 0000 0001 0661 2073. GRID: grid.411898.d
AD  - 2Research Institute for Diseases of the Chest, Graduate School of Medical 
      Sciences, Kyushu University, Fukuoka, Japan. ISNI: 0000 0001 2242 4849. GRID: 
      grid.177174.3
FAU - Araya, Jun
AU  - Araya J
AD  - 1Division of Respiratory Diseases, Department of Internal Medicine, Jikei 
      University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 
      Japan. ISNI: 0000 0001 0661 2073. GRID: grid.411898.d
FAU - Kuwano, Kazuyoshi
AU  - Kuwano K
AD  - 1Division of Respiratory Diseases, Department of Internal Medicine, Jikei 
      University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 
      Japan. ISNI: 0000 0001 0661 2073. GRID: grid.411898.d
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20181024
PL  - England
TA  - Inflamm Regen
JT  - Inflammation and regeneration
JID - 101479577
PMC - PMC6199723
OTO - NOTNLM
OT  - COPD
OT  - IPF
OT  - Mitophagy
OT  - PARK2
OT  - PINK1
COIS- Not applicableNot applicableThe authors declare that they have no competing 
      interests.Springer Nature remains neutral with regard to jurisdictional claims in 
      published maps and institutional affiliations.
EDAT- 2018/11/06 06:00
MHDA- 2018/11/06 06:01
PMCR- 2018/10/24
CRDT- 2018/11/03 06:00
PHST- 2018/05/27 00:00 [received]
PHST- 2018/07/02 00:00 [accepted]
PHST- 2018/11/03 06:00 [entrez]
PHST- 2018/11/06 06:00 [pubmed]
PHST- 2018/11/06 06:01 [medline]
PHST- 2018/10/24 00:00 [pmc-release]
AID - 77 [pii]
AID - 10.1186/s41232-018-0077-6 [doi]
PST - epublish
SO  - Inflamm Regen. 2018 Oct 24;38:18. doi: 10.1186/s41232-018-0077-6. eCollection 
      2018.