Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis.
Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition-mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Kenji
K
Kobayashi
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and araya@jikei.ac.jp.
Jun
J
Araya
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Shunsuke
S
Minagawa
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Hiromichi
H
Hara
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Nayuta
N
Saito
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Tsukasa
0000-0002-9533-7241
T
Kadota
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Nahoko
N
Sato
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Masahiro
M
Yoshida
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Kazuya
K
Tsubouchi
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Yusuke
Y
Kurita
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Saburo
S
Ito
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Yu
0000-0002-8916-7303
Y
Fujita
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Naoki
N
Takasaka
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Hirofumi
H
Utsumi
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Haruhiko
H
Yanagisawa
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Mitsuo
M
Hashimoto
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Hiroshi
H
Wakui
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Jun
J
Kojima
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Kenichiro
K
Shimizu
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Takanori
T
Numata
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Makoto
M
Kawaishi
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Yumi
Y
Kaneko
Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Hisatoshi
H
Asano
Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Makoto
M
Yamashita
Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Makoto
M
Odaka
Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Toshiaki
T
Morikawa
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Katsutoshi
K
Nakayama
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan; and.
Kazuyoshi
K
Kuwano
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D063306:Mitophagy / Q000502:physiology*; D058628:Myofibroblasts / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017479:Receptors, Platelet-Derived Growth Factor; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein