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

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, mitochondria-localized tumor suppressor. ► SIRT3 is a genomically expressed, mitochondrial-localized in vitro tumor suppressor ► Mice lacking SIRT3 develop ER/PR-positive invasive ductal mammary tumors ► SIRT3 is decreased in human breast cancer tumors and several other malignancies ► SIRT3 loss results in aberrant mitochondrial metabolism and genomic instability