PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses
Identifieur interne : 000770 ( Pmc/Curation ); précédent : 000769; suivant : 000771PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses
Auteurs : Marta Bueno [États-Unis] ; Daniel Zank [États-Unis] ; Ivette Buendia-Roldán [Mexique] ; Kaitlin Fiedler [États-Unis] ; Brenton G. Mays [États-Unis] ; Diana Alvarez [États-Unis] ; John Sembrat [États-Unis] ; Brian Kimball [États-Unis] ; Jordan K. Bullock [États-Unis] ; James L. Martin [États-Unis] ; Mehdi Nouraie [États-Unis] ; Brett A. Kaufman [États-Unis] ; Mauricio Rojas [États-Unis, Mexique] ; Annie Pardo [Mexique] ; Moisés Selman [Mexique] ; Ana L. Mora [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2019.
Abstract
We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.
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DOI: 10.1371/journal.pone.0218003
PubMed: 31170232
PubMed Central: 6553779
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Kaufman</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Rojas, Mauricio" sort="Rojas, Mauricio" uniqKey="Rojas M" first="Mauricio" last="Rojas">Mauricio Rojas</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Pardo, Annie" sort="Pardo, Annie" uniqKey="Pardo A" first="Annie" last="Pardo">Annie Pardo</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Distrito Federal</wicri:regionArea></affiliation></author><author><name sortKey="Selman, Moises" sort="Selman, Moises" uniqKey="Selman M" first="Moisés" last="Selman">Moisés Selman</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal</wicri:regionArea></affiliation></author><author><name sortKey="Mora, Ana L" sort="Mora, Ana L" uniqKey="Mora A" first="Ana L." last="Mora">Ana L. Mora</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31170232</idno><idno type="pmc">6553779</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553779</idno><idno type="RBID">PMC:6553779</idno><idno type="doi">10.1371/journal.pone.0218003</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000770</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000770</idno><idno type="wicri:Area/Pmc/Curation">000770</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000770</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses</title><author><name sortKey="Bueno, Marta" sort="Bueno, Marta" uniqKey="Bueno M" first="Marta" last="Bueno">Marta Bueno</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Zank, Daniel" sort="Zank, Daniel" uniqKey="Zank D" first="Daniel" last="Zank">Daniel Zank</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Buendia Roldan, Ivette" sort="Buendia Roldan, Ivette" uniqKey="Buendia Roldan I" first="Ivette" last="Buendia-Roldán">Ivette Buendia-Roldán</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal</wicri:regionArea></affiliation></author><author><name sortKey="Fiedler, Kaitlin" sort="Fiedler, Kaitlin" uniqKey="Fiedler K" first="Kaitlin" last="Fiedler">Kaitlin Fiedler</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Mays, Brenton G" sort="Mays, Brenton G" uniqKey="Mays B" first="Brenton G." last="Mays">Brenton G. Mays</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Alvarez, Diana" sort="Alvarez, Diana" uniqKey="Alvarez D" first="Diana" last="Alvarez">Diana Alvarez</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Sembrat, John" sort="Sembrat, John" uniqKey="Sembrat J" first="John" last="Sembrat">John Sembrat</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Kimball, Brian" sort="Kimball, Brian" uniqKey="Kimball B" first="Brian" last="Kimball">Brian Kimball</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Bullock, Jordan K" sort="Bullock, Jordan K" uniqKey="Bullock J" first="Jordan K." last="Bullock">Jordan K. Bullock</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Martin, James L" sort="Martin, James L" uniqKey="Martin J" first="James L." last="Martin">James L. Martin</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Nouraie, Mehdi" sort="Nouraie, Mehdi" uniqKey="Nouraie M" first="Mehdi" last="Nouraie">Mehdi Nouraie</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Kaufman, Brett A" sort="Kaufman, Brett A" uniqKey="Kaufman B" first="Brett A." last="Kaufman">Brett A. Kaufman</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Rojas, Mauricio" sort="Rojas, Mauricio" uniqKey="Rojas M" first="Mauricio" last="Rojas">Mauricio Rojas</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author><author><name sortKey="Pardo, Annie" sort="Pardo, Annie" uniqKey="Pardo A" first="Annie" last="Pardo">Annie Pardo</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Distrito Federal</wicri:regionArea></affiliation></author><author><name sortKey="Selman, Moises" sort="Selman, Moises" uniqKey="Selman M" first="Moisés" last="Selman">Moisés Selman</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal, México</addr-line></nlm:aff><country xml:lang="fr" wicri:curation="lc">Mexique</country><wicri:regionArea>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal</wicri:regionArea></affiliation></author><author><name sortKey="Mora, Ana L" sort="Mora, Ana L" uniqKey="Mora A" first="Ana L." last="Mora">Ana L. Mora</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ley, B" uniqKey="Ley B">B Ley</name></author><author><name sortKey="Collard, Hr" uniqKey="Collard H">HR Collard</name></author><author><name sortKey="King, Te" uniqKey="King T">TE King</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mora, Al" uniqKey="Mora A">AL Mora</name></author><author><name sortKey="Rojas, M" uniqKey="Rojas M">M Rojas</name></author><author><name sortKey="Pardo, A" uniqKey="Pardo A">A Pardo</name></author><author><name sortKey="Selman, M" uniqKey="Selman M">M Selman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Selman, M" uniqKey="Selman M">M Selman</name></author><author><name sortKey="Pardo, 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31170232</article-id><article-id pub-id-type="pmc">6553779</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0218003</article-id><article-id pub-id-type="publisher-id">PONE-D-19-07893</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>DNA</subject><subj-group><subject>Forms of DNA</subject><subj-group><subject>Mitochondrial DNA</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Nucleic acids</subject><subj-group><subject>DNA</subject><subj-group><subject>Forms of DNA</subject><subj-group><subject>Mitochondrial DNA</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Connective Tissue Cells</subject><subj-group><subject>Fibroblasts</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Connective Tissue</subject><subj-group><subject>Connective Tissue Cells</subject><subj-group><subject>Fibroblasts</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Connective Tissue</subject><subj-group><subject>Connective Tissue Cells</subject><subj-group><subject>Fibroblasts</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Epithelial Cells</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Epithelium</subject><subj-group><subject>Epithelial Cells</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Biological Tissue</subject><subj-group><subject>Epithelium</subject><subj-group><subject>Epithelial Cells</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Bioenergetics</subject><subj-group><subject>Energy-Producing Organelles</subject><subj-group><subject>Mitochondria</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Structures and Organelles</subject><subj-group><subject>Energy-Producing Organelles</subject><subj-group><subject>Mitochondria</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Cell biology</subject><subj-group><subject>Signal transduction</subject><subj-group><subject>Cell signaling</subject><subj-group><subject>Signaling cascades</subject><subj-group><subject>TGF-beta signaling cascade</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Developmental Biology</subject><subj-group><subject>Fibrosis</subject><subj-group><subject>Pulmonary Fibrosis</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Cell Signaling</subject><subj-group><subject>Membrane Receptor Signaling</subject><subj-group><subject>Immune Receptor Signaling</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses</article-title><alt-title alt-title-type="running-head">mtDNA drives profibrotic responses in AECII</alt-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-7140-9899</contrib-id><name><surname>Bueno</surname><given-names>Marta</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zank</surname><given-names>Daniel</given-names></name><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buendia-Roldán</surname><given-names>Ivette</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fiedler</surname><given-names>Kaitlin</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mays</surname><given-names>Brenton G.</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Alvarez</surname><given-names>Diana</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sembrat</surname><given-names>John</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kimball</surname><given-names>Brian</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bullock</surname><given-names>Jordan K.</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>James L.</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nouraie</surname><given-names>Mehdi</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kaufman</surname><given-names>Brett A.</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rojas</surname><given-names>Mauricio</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pardo</surname><given-names>Annie</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Selman</surname><given-names>Moisés</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mora</surname><given-names>Ana L.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Distrito Federal, México</addr-line></aff><aff id="aff005"><label>5</label><addr-line>The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></aff><aff id="aff007"><label>7</label><addr-line>McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Distrito Federal, México</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Mukhopadhyay</surname><given-names>Partha</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>National Institutes of Health, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>anamora@pitt.edu</email></corresp></author-notes><pub-date pub-type="epub"><day>6</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>14</volume><issue>6</issue><elocation-id>e0218003</elocation-id><history><date date-type="received"><day>19</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>22</day><month>5</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 Bueno et al</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Bueno et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0218003.pdf"></self-uri><abstract><p>We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.</p></abstract><funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000050</institution-id><institution>National Heart, Lung, and Blood Institute</institution></institution-wrap></funding-source><award-id>R01 HL131789-01</award-id><principal-award-recipient><name><surname>Mora</surname><given-names>Ana L.</given-names></name></principal-award-recipient></award-group><award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000050</institution-id><institution>National Heart, Lung, and Blood Institute</institution></institution-wrap></funding-source><award-id>R01 HL123766-01</award-id><principal-award-recipient><name><surname>Rojas</surname><given-names>Mauricio</given-names></name></principal-award-recipient></award-group><funding-statement>This study was supported by NIH 1 R01 HL131789-01 (ALM), NIH 1R01 HL123766-01 (MR). This work was also supported in part by the Vascular Medicine Institute at the University of Pittsburgh, the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania (ALM).</funding-statement></funding-group><counts><fig-count count="8"></fig-count><table-count count="0"></table-count><page-count count="20"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the manuscript and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the manuscript and its Supporting Information files.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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