TY - JOUR
T1 - Mitochondrial SKN-1/Nrf mediates a conserved starvation response
AU - Paek, Jennifer
AU - Lo, Jacqueline Y.
AU - Narasimhan, Sri Devi
AU - Nguyen, Tammy N.
AU - Glover-Cutter, Kira
AU - Robida-Stubbs, Stacey
AU - Suzuki, Takafumi
AU - Yamamoto, Masayuki
AU - Blackwell, T. Keith
AU - Curran, Sean P.
N1 - Funding Information:
We thank Chandra Tucker, Duke University for the C. elegans Y2H library (Developed by Maureen Barr's laboratory). We are grateful to Daniel Wai, Children's Hospital Los Angeles for analysis of Affymetrix microarray data. We also thank Drs. Caleb Finch, Alexander Soukas, and Shanshan Pang for critically reading the manuscript and all members of the Curran laboratory for technical support and fruitful discussions. S.P.C. conceived and designed the study. T.K.B. and M.Y. collaborated with SPC to plan and organize experiments. J.P., J.Y.L., S.D.N., T.N.N., K.G.C., S.R.S., T.S., and S.P.C. conducted the experiments. Some of the strains used in the study were obtained from the Caenorhabditis Genetics Center (CGC), which is supported by the National Institutes of Health—NCRR. Research in this study was supported by NIH R01GM62891 (T.K.B.) and R00AG032308 (S.P.C.). S.P.C. is an Ellison Medical Foundation Junior Scholar in Aging.
PY - 2012/10/3
Y1 - 2012/10/3
N2 - SKN-1/Nrf plays multiple essential roles in development and cellular homeostasis. We demonstrate that SKN-1 executes a specific and appropriate transcriptional response to changes in available nutrients, leading to metabolic adaptation. We isolated gain-of-function (gf) alleles of skn-1, affecting a domain of SKN-1 that binds the transcription factor MXL-3 and the mitochondrial outer membrane protein PGAM-5. These skn-1(gf) mutants perceive a state of starvation even in the presence of plentiful food. The aberrant monitoring of cellular nutritional status leads to an altered survival response in which skn-1(gf) mutants transcriptionally activate genes associated with metabolism, adaptation to starvation, aging, and survival. The triggered starvation response is conserved in mice with constitutively activated Nrf and may contribute to the tumorgenicity associated with activating Nrf mutations in mammalian somatic cells. Our findings delineate an evolutionarily conserved metabolic axis of SKN-1/Nrf, further establishing the complexity of this pathway.
AB - SKN-1/Nrf plays multiple essential roles in development and cellular homeostasis. We demonstrate that SKN-1 executes a specific and appropriate transcriptional response to changes in available nutrients, leading to metabolic adaptation. We isolated gain-of-function (gf) alleles of skn-1, affecting a domain of SKN-1 that binds the transcription factor MXL-3 and the mitochondrial outer membrane protein PGAM-5. These skn-1(gf) mutants perceive a state of starvation even in the presence of plentiful food. The aberrant monitoring of cellular nutritional status leads to an altered survival response in which skn-1(gf) mutants transcriptionally activate genes associated with metabolism, adaptation to starvation, aging, and survival. The triggered starvation response is conserved in mice with constitutively activated Nrf and may contribute to the tumorgenicity associated with activating Nrf mutations in mammalian somatic cells. Our findings delineate an evolutionarily conserved metabolic axis of SKN-1/Nrf, further establishing the complexity of this pathway.
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U2 - 10.1016/j.cmet.2012.09.007
DO - 10.1016/j.cmet.2012.09.007
M3 - Article
C2 - 23040073
AN - SCOPUS:84867040616
VL - 16
SP - 526
EP - 537
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 4
ER -