Download Project Summary / Abstract

Seok-Jo Kim, PhD.
Research Assistant Professor
Division of Pulmonary & Critical Care
Northwestern University Feinberg School of Medicine
Title
SIRT3 and Klotho, anti-aging molecules, attenuate oxidant-induced alveolar epithelial cell mtDNA damage
and in mediating apoptosis and pulmonary fibrosis
Abstract
Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically
important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) and inadequate repair
resulting from ‘exaggerated’ lung aging and mitochondrial dysfunction are critical determinants promoting lung
diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos
exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential
for oxidative phosphorylation. We have showed the evidence implicating that mtDNA damage induced by
oxidative stress, one of aging factor, promotes AEC apoptosis and pulmonary fibrosis. We focus on the
emerging role for linkage the aging factors (SIRT3 and Klotho) to mitochondrial integrity and mtDNA damage
repair. IPF lung AT2 cells have increased MnSODK68 acetylation, which is a major target by SIRT3, compared
to controls. Asbestos and H2O2 diminished AEC SIRT3 and Klotho protein expression and increased
mitochondrial protein acetylation, including MnSODK68. The over-expression of these aging factors reduced
oxidant-induced AEC OGG1K338/341 acetylation, mtDNA damage and apoptosis whereas their silencing
promoted these effects. Asbestos- or bleomycin- induced lung fibrosis, AEC mtDNA damage and apoptosis in
WT mice was amplified in Sirt3-/- and kl/+ mice. In addition, we show that Klotho attenuates oxidant-induced
AEC mtDNA damage and apoptosis via mechanisms dependent upon AKT activation arising from upstream
fibroblast growth factor receptor 1 (FGFR1) activation. Our findings suggest that SIRT3 and Klotho preserve
AEC mtDNA integrity in the setting of oxidative stress necessary for preventing apoptosis and asbestos-induced
lung fibrosis. We reason that strategies aimed at augmenting AEC Klotho levels may be an innovative approach
for mitigating age-related diseases, including pulmonary fibrosis and lung cancer.