SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis

Renea P. Jablonski, Seok Jo Kim, Paul Cheresh, David B. Williams, Luisa Morales-Nebreda, Yuan Cheng, Anjana Yeldandi, Sangeeta Bhorade, Annie Pardo, Moises Selman, Karen Ridge, David Gius, G. R.Scott Budinger, David W. Kamp*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

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 deacetylatingmanganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase.We reasoned that SIRT3 deficiency occurs in fibrotic lungs and thereby augmentsAECmtDNAdamage and apoptosis. Human lungswere assessed by using immunohistochemistry for SIRT3 activity via acetylated MnSODK68. Murine AECSIRT3 and cleaved caspase-9 (CC-9) expression were assayedby immunoblottingwith or withoutSIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosis via ELISA. 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 increasedMnSODK68 acetylation compared with controls. Asbestos and H2O2 diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSODK68. SIRT3 enforced expression reduced oxidant-induced AEC OGG1K338/341 acetylation, 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 in Sirt3-/- animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and lung fibrosis.

Original languageEnglish (US)
Pages (from-to)2520-2532
Number of pages13
JournalFASEB Journal
Volume31
Issue number6
DOIs
Publication statusPublished - Jun 2017

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Keywords

  • Oxidative stress
  • Pulmonary fibrosis
  • Sirtuin 3

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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