SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression

Kristi Muldoon Jacobs, J. Daniel Pennington, Kheem S. Bisht, Nukhet Aykin-Burns, Hyun Seok Kim, Mark Mishra, Lunching Sun, Phuongmai Nguyen, Bong Hyun Ahn, Jaime Leclerc, Chu Xia Deng, Douglas R. Spitz, David Gius*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

Cellular longevity is a complex process relevant to age-related diseases including but not limited to chronic illness such as diabetes and metabolic syndromes. Two gene families have been shown to play a role in the genetic regulation of longevity; the Sirtuin and FOXO families. It is also established that nuclear Sirtuins interact with and under specific cellular conditions regulate the activity of FOXO gene family proteins. Thus, we hypothesize that a mitochondrial Sirtuin (SIRT3) might also interact with and regulate the activity of the FOXO proteins. To address this we used HCT116 cells overexpressing either wild-type or a catalytically inactive dominant negative SIRT3. For the first time we establish that FOXO3a is also a mitochondrial protein and forms a physical interaction with SIRT3 in mitochondria. Overexpression of a wild-type SIRT3 gene increase FOXO3a DNA-binding activity as well as FOXO3a dependent gene expression. Biochemical analysis of HCT116 cells over expressing the deacetylation mutant, as compared to wild-type SIRT3 gene, demonstrated an overall oxidized intracellular environment, as monitored by increase in intracellular superoxide and oxidized glutathione levels. As such, we propose that SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway.

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalInternational Journal of Biological Sciences
Volume4
Issue number5
DOIs
StatePublished - Sep 5 2008

Keywords

  • FOXO3a
  • Gene expression
  • SIRT3
  • Superoxide

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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