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

Hyun Seok Kim, Krish Patel, Kristi Muldoon-Jacobs, Kheem S. Bisht, Nukhet Aykin-Burns, J. Daniel Pennington, Riet van der Meer, Phuongmai Nguyen, Jason Savage, Kjerstin M. Owens, Athanassios Vassilopoulos, Ozkan Ozden, Seong Hoon Park, Keshav K. Singh, Sarki A. Abdulkadir, Douglas R. Spitz, Chu Xia Deng*, David Gius

*Corresponding author for this work

Research output: Contribution to journalArticle

528 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)41-52
Number of pages12
JournalCancer Cell
Volume17
Issue number1
DOIs
StatePublished - Jan 19 2010

Keywords

  • CELLCYCLE
  • PROTEINS

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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