SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression.
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.
Jacobs
Kristi Muldoon
KM
Molecular Radiation Oncology, Center for Cancer Research, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. giusd@mail.nih.gov
Pennington
J Daniel
JD
Bisht
Kheem S
KS
Aykin-Burns
Nukhet
N
Kim
Hyun-Seok
HS
Mishra
Mark
M
Sun
Lunching
L
Nguyen
Phuongmai
P
Ahn
Bong-Hyun
BH
Leclerc
Jaime
J
Deng
Chu-Xia
CX
Spitz
Douglas R
DR
Gius
David
D
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D019803:Glutathione Disulfide / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D056566:Sirtuin 3; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D024101:Mitochondrial Proteins; D013481:Superoxides; D013482:Superoxide Dismutase; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D037761:Sirtuins; D019803:Glutathione Disulfide
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