TY - JOUR
T1 - SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis
AU - Jablonski, Renea Poppino
AU - Kim, Seokjo
AU - Cheresh, Paul
AU - Williams, David B.
AU - Morales-Nebreda, Luisa
AU - Cheng, Yuan
AU - Yeldandi, Anjana
AU - Bhorade, Sangeeta Maruti
AU - Pardo, Annie
AU - Selman, Moises
AU - Ridge, Karen
AU - Gius, David R
AU - Budinger, G. R.Scott
AU - Kamp, David W.
N1 - Publisher Copyright:
© FASEB.
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
KW - Oxidative stress
KW - Pulmonary fibrosis
KW - Sirtuin 3
UR - http://www.scopus.com/inward/record.url?scp=85020241929&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020241929&partnerID=8YFLogxK
U2 - 10.1096/fj.201601077R
DO - 10.1096/fj.201601077R
M3 - Article
C2 - 28258190
AN - SCOPUS:85020241929
SN - 0892-6638
VL - 31
SP - 2520
EP - 2532
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -