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Mitochondrial SKN-1/Nrf mediates a conserved starvation response
Jennifer Paek1, Jacqueline Y Lo, Sri Devi Narasimhan
1Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Cell Metabolism
|October 9, 2012
Summary
Gain-of-function SKN-1 (also known as Nrf) mutations cause cells to incorrectly sense starvation, activating survival genes. This conserved metabolic pathway may link to cancer in mammals.
Area of Science:
- Cellular homeostasis
- Metabolic adaptation
- Developmental biology
Background:
- SKN-1/Nrf is crucial for cellular homeostasis and development.
- SKN-1 regulates transcriptional responses to nutrient availability.
- Understanding SKN-1's role in metabolic adaptation is key.
Purpose of the Study:
- To investigate the function of SKN-1/Nrf in nutrient sensing and metabolic adaptation.
- To identify specific domains of SKN-1 involved in its regulatory functions.
- To explore the evolutionary conservation and implications of SKN-1/Nrf signaling.
Main Methods:
- Isolation and characterization of skn-1 gain-of-function (gf) alleles.
- Analysis of SKN-1 binding interactions with MXL-3 and PGAM-5.
- Transcriptional profiling of skn-1(gf) mutants under nutrient-rich conditions.
- Comparative analysis of Nrf pathway conservation in mice.
Main Results:
- Gain-of-function skn-1 alleles cause constitutive sensing of starvation.
- Mutants activate genes related to metabolism, starvation survival, aging, and longevity.
- SKN-1 interacts with transcription factor MXL-3 and mitochondrial protein PGAM-5.
- The triggered starvation response is conserved in mice with activated Nrf.
Conclusions:
- SKN-1/Nrf mediates a conserved metabolic axis controlling nutrient sensing and survival.
- Aberrant SKN-1 signaling can inappropriately activate starvation responses.
- Constitutively active Nrf may contribute to tumorgenesis in mammalian cells.
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