SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Abstract

Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is TGF-β1-mediated transformation of fibroblasts into myofibroblasts, a cell capable of synthesizing extracellular matrix. Here we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the pro-fibrotic TGF-β1 signaling. We found that Sirt3-KO mice with age develop tissue fibrosis of multiple organs including heart, liver, kidney and lungs; but not the whole body SIRT3 overexpressing mice. SIRT3 deficiency caused induction of TGFβ1 expression and hyper-acetylation of GSK3β at K15 residue, which negatively regulated GSK3β activity to phosphorylate the substrates, Smad3 and β-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3β, and thereby blocked the TGFβ1 signaling and tissue fibrosis. These data reveals a new role of SIRT3 to negatively regulate the aging-associated tissue fibrosis, and discloses a novel phosphorylation-independent mechanism controlling the catalytic activity of GSK3β.