SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

Abstract

SUMMARY The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3−/− mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3−/− MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3−/− MEFs and reverses the tumor permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3−/− mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondrial localized tumor suppressor.

Post-translational modifications of FOXO family proteins

“…Furthermore, SIRT3 is the major deacetylase in the mitochondrion (99). SIRT3 deacetylates FOXO3a, which strengthens the DNA-binding of FOXO3a, but does not change the mitochondrial location of FOXO3a (100). It has been demonstrated that FOXO3a forms a complex with SIRT3 and mitochondrial RNA polymerase, binding to mitochondrial DNA, and further increasing the expression of oxidative phosphorylation-associated proteins, ultimately, increasing mitochondrial respiration (59).…”

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

“…It regulates mitochondrial activity by ROS in many cell types and modulates CREB phosphorylation and fat metabolism (Shi et al ., 2005; Hirschey et al ., 2010; Kim et al ., 2010). Importantly, SIRT3 has an essential role in enhancing the mitochondrial antioxidant glutathione, which could contribute to reduce aging in mammals (Someya et al ., 2010).…”

Roles of SIRT3 in heart failure: from bench to bedside

“…SIRT3 is a soluble mitochondrial protein highly expressed in mitochondrial rich tissues and also plays critical roles related to tumor suppression, cellular stress, fat acid metabolism, oxidative stress response, and age-associated hearing loss (Hirschey et al, 2010;Kim et al, 2010;Someya et al, 2010). Lombard et al (2007) found that no abnormalities were identified in SIRT3-deficient mice under non-stress conditions; however, the hyperacetylation of mitochondrial proteins was observed when stress was applied.…”

“…Fortunately, SIRT3 has been demonstrated to participate in numerous biological processes including anti-oxidation reactions, cell survival, and mitochondrial protection, all of which could contribute to the treatment of ischemic heart disease (Kim et al, 2010;Someya et al, 2010;Dittenhafer-Reed et al, 2015). Since loss of cardiomyocytes due to cell death is the main cause of cardiac dysfunction following MI, inhibition of apoptosis or necrosis is a critical necessity.…”