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

doi:10.7150/ijbs.4.291

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

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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, …

International journal of biological sciences, Vol.4(5), pp.291-299

09/05/2008

DOI: 10.7150/ijbs.4.291

PMCID: PMC2532794

PMID: 18781224

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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.

Gene Expression

Transfection

Animals

Cercopithecus aethiops

Chromatin Immunoprecipitation

COS Cells

Forkhead Box Protein O3

Forkhead Transcription Factors - genetics

Forkhead Transcription Factors - metabolism

Glutathione Disulfide - metabolism

HCT116 Cells

Humans

Mitochondria - metabolism

Mitochondrial Proteins - genetics

Mitochondrial Proteins - metabolism

Protein Binding

Sirtuin 3

Sirtuins - genetics

Sirtuins - metabolism

Superoxide Dismutase - metabolism

Superoxides - metabolism

Details

Title: Subtitle: SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression
Creators: Kristi Muldoon Jacobs - National Institutes of Health
J Daniel Pennington - National Institutes of Health
Kheem S Bisht - National Institutes of Health
Nukhet Aykin-Burns - University of Iowa
Hyun-Seok Kim - University of Life Sciences
Mark Mishra - National Institutes of Health
Lunching Sun - National Institutes of Health
Phuongmai Nguyen - National Institutes of Health
Bong-Hyun Ahn - National Institutes of Health
Jaime Leclerc - National Institutes of Health
Chu-Xia Deng - National Institutes of Health
Douglas R Spitz - University of Iowa
David Gius - National Institutes of Health
Resource Type: Journal article
Publication Details: International journal of biological sciences, Vol.4(5), pp.291-299
DOI: 10.7150/ijbs.4.291
PMID: 18781224
PMCID: PMC2532794
NLM abbreviation: Int J Biol Sci
ISSN: 1449-2288
eISSN: 1449-2288
Grant note: R01 HL51469 / NHLBI NIH HHS P20 CA091709 / NCI NIH HHS P01-CA66081 / NCI NIH HHS Intramural NIH HHS R01-CA100045 / NCI NIH HHS R01 HL051469 / NHLBI NIH HHS F32 CA110611 / NCI NIH HHS P01 CA066081 / NCI NIH HHS P01CA66081 / NCI NIH HHS F32-CA110611 / NCI NIH HHS R01 CA100045 / NCI NIH HHS P20 CA91709 / NCI NIH HHS
Language: English
Date published: 09/05/2008
Academic Unit: Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984313860002771

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