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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.