Int J Biol Sci 2008; 4(5):291-299. doi:10.7150/ijbs.4.291

Research Paper

SIRT3 interacts with the daf-16 homolog FOXO3a in the Mitochondria, as well as increases FOXO3a Dependent Gene expression

Kristi Muldoon Jacobs 1 *, J. Daniel Pennington 1 *, Kheem S. Bisht1, Nukhet Aykin-Burns 2, Hyun-Seok Kim 3, Mark Mishra1, Lunching Sun 1, Phuongmai Nguyen 1, Bong-Hyun Ahn 4, Jaime Leclerc 1, Chu-Xia Deng 3, Douglas R. Spitz 2, David Gius 1 ✉

1. Molecular Radiation Oncology, Center for Cancer Research, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
2. Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA
3. Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, MD
4. Cardiology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD
* The first two authors contributed equally to this paper.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
Jacobs KM, Pennington JD, Bisht KS, Aykin-Burns N, Kim HS, Mishra M, Sun L, Nguyen P, Ahn BH, Leclerc J, Deng CX, Spitz DR, Gius D. SIRT3 interacts with the daf-16 homolog FOXO3a in the Mitochondria, as well as increases FOXO3a Dependent Gene expression. Int J Biol Sci 2008; 4(5):291-299. doi:10.7150/ijbs.4.291. Available from

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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.

Keywords: SIRT3, FOXO3a, gene expression, Superoxide