title: SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.
abstract: Alveolar epithelial cell (AEC) mitochondrial dysfunction and apoptosis are important in idiopathic pulmonary fibrosis and asbestosis. Sirtuin 3 (SIRT3) detoxifies mitochondrial reactive oxygen species, in part, by deacetylating manganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase. We reasoned that SIRT3 deficiency occurs in fibrotic lungs and thereby augments AEC mtDNA damage and apoptosis. Human lungs were assessed by using immunohistochemistry for SIRT3 activityviaacetylated MnSODK68Murine AEC SIRT3 and cleaved caspase-9 (CC-9) expression were assayed by immunoblotting with or without SIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosisviaELISA. Pulmonary fibrosis after asbestos or bleomycin exposure was evaluated in 129SJ/wild-type and SIRT3-knockout mice (Sirt3-/-) by using fibrosis scoring and lung collagen levels. Idiopathic pulmonary fibrosis lung alveolar type II cells have increased MnSODK68acetylation compared with controls. Asbestos and H2O2diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSODK68SIRT3 enforced expression reduced oxidant-induced AEC OGG1K338/341acetylation, mtDNA damage, and apoptosis, whereas SIRT3 silencing promoted these effects. Asbestos- or bleomycin-induced lung fibrosis, AEC mtDNA damage, and apoptosis in wild-type mice were amplified inSirt3-/-animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and lung fibrosis.-Jablonski, R. P., Kim, S.-J., Cheresh, P., Williams, D. B., Morales-Nebreda, L., Cheng, Y., Yeldandi, A., Bhorade, S., Pardo, A., Selman, M., Ridge, K., Gius, D., Budinger, G. R. S., Kamp, D. W. SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Renea P
authors.initials: RP
authors.lastname: Jablonski
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Seok-Jo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Yeldandi
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Bhorade
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, México City, Mexico.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México City, Mexico.
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ridge
authors.affiliation: Department of Radiation Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: G R Scott
authors.initials: GRS
authors.lastname: Budinger
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA; d-kamp@northwestern.edu.|Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
mesh_terms: D000072283:A549 Cells; D056809:Alveolar Epithelial Cells / Q000473:pathology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000502:physiology*; D001194:Asbestos / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000633:toxicity; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D016877:Oxidants; C525046:Sirt3 protein, mouse; D001761:Bleomycin; D001194:Asbestos; D056566:Sirtuin 3
keywords: oxidative stress; pulmonary fibrosis; sirtuin 3