The SirT3 Divining Rod Points to Oxidative Stress Eric L. Bell, Leonard Guarente  Molecular Cell  Volume 42, Issue 5, Pages 561-568 (June 2011) DOI: 10.1016/j.molcel.2011.05.008 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 SirT3 Is Necessary for Protection from Hearing Loss by CR Aging induces ROS damage to inner ear cochlea neurons. In conditions of calorie restriction (CR), SirT3 inhibits ROS-mediated damage of cochlea neurons to delay hearing loss. Molecular Cell 2011 42, 561-568DOI: (10.1016/j.molcel.2011.05.008) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 2 SirT3 Protects against Damage from Mitochondrially Derived ROS ROS are primarily generated by complex I (matrix) and complex III (matrix, intermembrane space, and cytosol). Superoxides (O2·) localized to the matrix are detoxified by manganese superoxide dismutase (SOD2) into hydrogen peroxide (H2O2), which is subsequently converted into water by glutathione peroxidase (GPX). GPX requires reduced glutathione (GSH) for enzymatic activity. Oxidized glutathione (GSSH) is reduced by glutathione reductase (GSR), which requires NADPH. NADPH is generated from NADP+ by isocitrate dehydrogenase 2 (IDH2). By activating SOD2 and IDH2 and inhibiting ROS generation by complex III and potentially complex I, SirT3 may be a major determinant of oxidative damage in cells. Molecular Cell 2011 42, 561-568DOI: (10.1016/j.molcel.2011.05.008) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 3 SirT3 Acts as a Tumor Suppressor through the Regulation of ROS (A) SirT3 suppresses mitochondrially generated ROS to reduce DNA damage and genomic instability. This may be important in the initiation of tumorigenesis. (B) By suppressing mitochondrially derived ROS, SirT3 also inhibits a signaling cascade resulting in the stabilization and activation of HIF-1α protein and activation of transcriptional targets that promote aerobic glycolysis, angiogenesis, and the progression of tumorigenesis. Molecular Cell 2011 42, 561-568DOI: (10.1016/j.molcel.2011.05.008) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 4 Model by which SirT1 and SirT3 Cooperate during CR In conditions of decreased caloric intake, SirT1 protein levels and activity are increased, leading to the deacetylation and activation of PGC-1α. Transactivation of ERRα by PGC-1α increases transcription of SirT3, resulting in a decrease in ROS and the promotion of healthy aging. Molecular Cell 2011 42, 561-568DOI: (10.1016/j.molcel.2011.05.008) Copyright © 2011 Elsevier Inc. Terms and Conditions