title: Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD.
abstract: The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cloonan
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.forename: Abhiram R
authors.initials: AR
authors.lastname: Bhashyam
authors.forename: Morgan
authors.initials: M
authors.lastname: Cervo
authors.forename: Tohru
authors.initials: T
authors.lastname: Kitada
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Mahmood
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.forename: Shu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D034281:Dynamins / Q000502:physiology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D063306:Mitophagy / Q000502:physiology*; D009336:Necrosis; D011494:Protein Kinases / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology*; D052999:Quinazolinones / Q000494:pharmacology; D012906:Smoke / Q000009:adverse effects; D014026:Nicotiana / Q000009:adverse effects; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D034281:Dynamins; D011494:Protein Kinases; D052999:Quinazolinones; D012906:Smoke; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C111567:parkin protein; C486391:Dnm1l protein, mouse
references.citation: Am J Respir Crit Care Med. 2001 Apr;163(5):1256-76
references.pmid: 11316667
references.citation: Am J Respir Cell Mol Biol. 2007 Apr;36(4):409-17
references.pmid: 17079780
references.citation: Autophagy. 2011 Mar;7(3):266-78
references.pmid: 21187721
references.citation: Cell. 2009 Jun 12;137(6):1100-11
references.pmid: 19524512
references.citation: Autophagy. 2012 Jan;8(1):6-17
references.pmid: 22170155
references.citation: Autophagy. 2013 Sep;9(9):1321-33
references.pmid: 23800795
references.citation: Trends Neurosci. 2014 Jun;37(6):315-24
references.pmid: 24735649
references.citation: Biochim Biophys Acta. 2013 May;1833(5):1256-68
references.pmid: 23434681
references.citation: Science. 2011 Aug 26;333(6046):1109-12
references.pmid: 21868666
references.citation: Aging (Albany NY). 2012 Jun;4(6):393-401
references.pmid: 22713507
references.citation: J Biol Chem. 2003 Oct 31;278(44):43628-35
references.pmid: 12930822
references.citation: Nature. 2011 Dec 1;480(7375):113-7
references.pmid: 22020285
references.citation: Cell Rep. 2013 Nov 27;5(4):878-85
references.pmid: 24268776
references.citation: J Clin Invest. 2013 Dec;123(12):5212-30
references.pmid: 24200693
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Nov 1;303(9):L748-57
references.pmid: 22983353
references.citation: J Clin Invest. 2010 Apr;120(4):1310-23
references.pmid: 20200450
references.citation: Eur Respir J. 2003 Oct;22(4):672-88
references.pmid: 14582923
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16677-82
references.pmid: 18946037
references.citation: PLoS One. 2013 Oct 17;8(10):e77713
references.pmid: 24147064
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14
references.pmid: 21179058
references.citation: EMBO J. 2008 Jan 23;27(2):433-46
references.pmid: 18200046
references.citation: Science. 2004 Jun 4;304(5676):1500-2
references.pmid: 15131264
references.citation: EMBO Rep. 2013 Feb;14(2):143-51
references.pmid: 23337627
references.citation: Cell Rep. 2014 Apr 24;7(2):476-487
references.pmid: 24703837
references.citation: J Appl Physiol (1985). 2001 Mar;90(3):1111-7
references.pmid: 11181627
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: Eur Respir J. 2009 May;33(5):1045-52
references.pmid: 19129279
references.citation: Eur Respir J. 2007 Apr;29(4):643-50
references.pmid: 17182653
references.citation: Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1924-31
references.pmid: 21890690
references.citation: Nature. 2011 Sep 14;477(7364):335-9
references.pmid: 21921917
references.citation: Autophagy. 2013 Nov 1;9(11):1897-9
references.pmid: 24149061
references.citation: Nat Cell Biol. 2011 May;13(5):589-98
references.pmid: 21478857
references.citation: Cell Death Differ. 2013 Jan;20(1):21-30
references.pmid: 22722335
references.citation: Mol Biol Cell. 2013 Apr;24(8):1153-62
references.pmid: 23427266
references.citation: Autophagy. 2013 Nov 1;9(11):1862-75
references.pmid: 24150213
references.citation: Hum Mol Genet. 2009 Oct 15;18(R2):R169-76
references.pmid: 19808793
references.citation: Autophagy. 2013 Nov 1;9(11):1750-7
references.pmid: 24149988
references.citation: Nat Cell Biol. 2011 Aug 07;13(9):1108-15
references.pmid: 21822277
references.citation: Mol Biol Cell. 2001 Aug;12(8):2245-56
references.pmid: 11514614
references.citation: Cell Death Differ. 2012 Jan;19(1):107-20
references.pmid: 21760595
references.citation: Am J Respir Crit Care Med. 2007 Sep 15;176(6):532-55
references.pmid: 17507545
references.citation: Hum Mol Genet. 2012 Nov 15;21(22):4888-903
references.pmid: 22872702
references.citation: Cell. 2011 Nov 11;147(4):728-41
references.pmid: 22078875
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11364-9
references.pmid: 18687901
references.citation: Semin Immunopathol. 2010 Dec;32(4):431-6
references.pmid: 20814791
references.citation: J Cell Biol. 2008 Dec 1;183(5):795-803
references.pmid: 19029340
references.citation: PLoS One. 2012;7(3):e32388
references.pmid: 22479323
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18880-5
references.pmid: 20956295
references.citation: PLoS Biol. 2010 Jan 26;8(1):e1000298
references.pmid: 20126261
references.citation: N Engl J Med. 2000 Jul 27;343(4):269-80
references.pmid: 10911010
references.citation: Nature. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Nat Rev Mol Cell Biol. 2010 Dec;11(12):872-84
references.pmid: 21102612
references.citation: Biochim Biophys Acta. 2012 Dec;1823(12):2297-310
references.pmid: 22917578
references.citation: Cell. 2012 Jan 20;148(1-2):213-27
references.pmid: 22265413
references.citation: Nat Chem Biol. 2012 Oct;8(10):831-8
references.pmid: 22922758
references.citation: Nat Rev Drug Discov. 2012 Sep;11(9):709-30
references.pmid: 22935804
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Nov 15;305(10):L737-46
references.pmid: 24056969
references.citation: N Engl J Med. 2013 Feb 14;368(7):651-62
references.pmid: 23406030
references.citation: Health Educ Behav. 2011 Oct;38(5):433-40
references.pmid: 21558465
references.citation: Nature. 2011 Jan 20;469(7330):323-35
references.pmid: 21248839
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11441-6
references.pmid: 17563363
references.citation: J Biol Chem. 2012 Jun 15;287(25):21110-20
references.pmid: 22556413
references.citation: Science. 2009 Jul 17;325(5938):332-6
references.pmid: 19498109
references.citation: Nature. 2011 Jul 31;477(7364):330-4
references.pmid: 21804564
references.citation: Chem Biol. 2011 Aug 26;18(8):1042-52
references.pmid: 21867919
references.citation: Autophagy. 2011 May;7(5):457-65
references.pmid: 21150268
references.citation: Int Rev Cell Mol Biol. 2011;289:1-35
references.pmid: 21749897
references.citation: Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14
references.pmid: 20823910
references.citation: Methods Enzymol. 2009;453:197-216
references.pmid: 19216908
references.citation: PLoS One. 2008 Oct 02;3(10):e3316
references.pmid: 18830406
references.citation: Cell. 2012 Jan 20;148(1-2):228-43
references.pmid: 22265414