GO:0042149 cellular response to glucose starvation: Metabolic Stress Signaling, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0042149 describes how a cell changes its state or activity when glucose is deprived, including shifts in metabolism, gene expression, secretion and movement [1,2,6].
• The AMPK-mTOR axis is a central regulator: AMPK directly phosphorylates Ulk1 to trigger autophagy under glucose limitation, while mTOR is inhibited.
• Glucose starvation rewires gene expression through epigenetic marks such as histone lysine beta-hydroxybutyrylation, linking metabolism to chromatin.
• Glucose limitation can induce disulfidptosis, a cell death mode dependent on SLC7A11 and endoplasmic reticulum stress, with therapeutic implications for cancer.
• The response is conserved across organisms, from fission yeast tau phosphorylation and stress responses to mammalian fibroblast metabolic adaptation [6,7].
• Key experimental approaches include CRISPR knockout/knock-in models, phospho-signaling assays, metabolomics, RNA-seq and autophagy flux measurements [1,2,8].
Description
Cellular response to glucose starvation (GO:0042149) is the collection of molecular and cellular changes that occur when a cell is deprived of glucose, its preferred carbon source [1,2,6]. This process is fundamental to how cells maintain energy homeostasis, survive nutrient stress, and decide between adaptation and death. It is highly relevant to cancer biology, metabolic disease, neurodegeneration and autophagy research because glucose availability fluctuates in tumors, ischemic tissues and fasting states [4,6,8]. Understanding GO:0042149 helps researchers interpret how cells rewire metabolism, activate stress kinases, alter gene expression and trigger quality-control pathways [1,3,5]. The term is defined in QuickGO as any process that results in a change in state or activity of a cell as a result of deprivation of glucose, covering movement, secretion, enzyme production and gene expression [1,2]. This article integrates authoritative ontology information with verified PubMed literature to provide a research-grade overview of the genes, mechanisms, disease links and experimental models associated with GO:0042149.
cellular response to glucose starvation At A Glance
| GO ID | GO:0042149 |
|---|---|
| GO term | cellular response to glucose starvation |
| Ontology | biological_process |
| Synonym | None listed in QuickGO |
| Major function | Coordinated cellular adaptation to glucose deprivation, including metabolic rewiring, autophagy, gene expression changes and stress responses |
| Key regulators | AMPK, mTOR, Ulk1, FoxO3, SLC7A11, IDH2, FicD |
| Associated processes | Autophagy, energy stress signaling, histone modification, disulfidptosis, gluconeogenesis/glycolysis |
| Disease relevance | Cancer metabolism, neurodegeneration, metabolic disorders, ferroptosis and disulfidptosis-related cell death |
| Research methods | CRISPR KO/KI, phospho-proteomics, RNA-seq, metabolomics, autophagy flux assays, imaging |
What Is GO:0042149?
In simple terms, GO:0042149 is the cellular program that switches on when glucose runs out. It includes all the changes a cell makes in its state or activity, such as altering enzyme production, gene expression, secretion, movement and metabolism, in response to glucose deprivation. The QuickGO definition emphasizes that the response is triggered specifically by lack of glucose and can involve many downstream cellular systems, including energy-sensing kinases, autophagy, epigenetic regulation and stress-response pathways [1,2,3].
Why Is cellular response to glucose starvation Important in Cell Biology?
GO:0042149 is important because glucose starvation is a common physiological and pathological stress that determines cell fate. In tumors, poor vascularization creates glucose-poor regions where cancer cells must adapt or die, making this process central to oncology and drug resistance [4,6]. In metabolic tissues, the response controls gluconeogenesis and glycolysis through regulators such as IDH2. In the brain and in aging, glucose deprivation contributes to stress responses and protein phosphorylation changes relevant to neurodegeneration. The pathway also intersects with autophagy, ferroptosis and disulfidptosis, offering targets for therapeutic intervention [1,4,8]. Because it integrates energy sensing, transcription, translation and cell death, GO:0042149 is a high-value area for CRISPR functional genomics and drug discovery.
• Glucose starvation activates AMPK, which phosphorylates Ulk1 to initiate autophagy and promote survival.
• mTOR inhibition under glucose limitation coordinates growth arrest with catabolic metabolism.
• Histone lysine beta-hydroxybutyrylation links glucose starvation to epigenetic gene regulation.
• SLC7A11-dependent disulfidptosis is a glucose-limitation-induced cell death mechanism relevant to cancer therapy.
• IDH2 regulates glycolysis and gluconeogenesis, connecting mitochondrial metabolism to glucose homeostasis.
• FicD sensitizes cells to glucose fluctuations, highlighting AMPylation in metabolic stress.
• Glucose deprivation induces tau phosphorylation and cellular stress in fission yeast, linking metabolism to neurodegeneration-related proteins.
• AMPK/FoxO3 signaling under energy stress modulates mitochondria-associated ferroptosis.
• Transformed fibroblasts show distinct responses to glucose and glutamine deprivation, useful for metabolic modeling.
• The pathway is conserved and can be studied across yeast, mouse and human cell models [2,7].
What Happens During cellular response to glucose starvation?
Energy sensing and AMPK activation
In simple terms: When glucose is low, the cell's energy gauge AMPK turns on.
Glucose deprivation increases the AMP/ATP ratio, activating AMPK. AMPK then phosphorylates downstream targets to restore energy balance, including Ulk1 at sites that trigger autophagy. This kinase cascade is an early and central event in GO:0042149 and coordinates survival with metabolic adaptation [1,8].
Autophagy induction via Ulk1 phosphorylation
In simple terms: The cell starts recycling its own components for energy.
AMPK directly phosphorylates Ulk1, while mTOR, which normally suppresses autophagy, is inhibited under glucose starvation. This dual regulation activates the Ulk1 complex and initiates autophagosome formation, allowing the cell to degrade proteins and organelles for energy. Autophagy is a hallmark output of GO:0042149 and is essential for survival during prolonged glucose limitation [1,8].
Metabolic rewiring and epigenetic changes
In simple terms: The cell changes its metabolism and how genes are read.
Glucose starvation alters central carbon metabolism and can change levels of metabolites such as beta-hydroxybutyrate, which modifies histones through lysine beta-hydroxybutyrylation. This epigenetic mark regulates gene expression in response to metabolic state. IDH2 also plays a role in balancing glycolysis and gluconeogenesis, linking mitochondrial metabolism to the glucose starvation response.
Stress responses and cell death decisions
In simple terms: If the stress is too strong, the cell may die in a controlled way.
Glucose limitation can induce endoplasmic reticulum stress and, in cells dependent on SLC7A11, trigger disulfidptosis, a form of cell death driven by disulfide stress. Energy stress also modulates ferroptosis through AMPK/FoxO3 signaling. These pathways determine whether a cell adapts or dies under glucose deprivation, with major implications for cancer therapy [4,8].
Conserved stress responses across organisms
In simple terms: Similar responses occur in yeast and human cells.
In fission yeast, glucose starvation induces tau phosphorylation and a cellular stress response, showing conservation of metabolic stress signaling. In human transformed fibroblasts, glucose and glutamine deprivation trigger distinct adaptive responses. FicD in mouse embryonic fibroblasts sensitizes cells to glucose fluctuations, further demonstrating conserved mechanisms.
Key Genes Involved in GO:0042149 cellular response to glucose starvation
The following genes and proteins are experimentally implicated in the cellular response to glucose starvation (GO:0042149) based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| AMPK | Energy sensor kinase activated by glucose deprivation | Central regulator of autophagy and metabolism [1,8] |
| Ulk1 | Autophagy-initiating kinase phosphorylated by AMPK | Direct link between energy stress and autophagy |
| mTOR | Growth regulator inhibited under glucose starvation | Coordinates growth arrest with catabolism |
| FoxO3 | Transcription factor downstream of AMPK | Modulates ferroptosis under energy stress |
| SLC7A11 | Cystine/glutamate antiporter | Mediates disulfidptosis upon glucose limitation |
| IDH2 | Mitochondrial isocitrate dehydrogenase | Regulates glycolysis and gluconeogenesis |
| FicD | AMPylase enzyme | Sensitizes cells to glucose fluctuations |
| Tau | Microtubule-associated protein | Phosphorylated under glucose starvation in yeast |
| Histone H3 | Chromatin protein | Target of beta-hydroxybutyrylation under metabolic stress |
| Glutamine metabolism genes | Alternative carbon source utilization | Response to glucose and glutamine deprivation |
| ER stress sensors | Unfolded protein response | Cooperate with SLC7A11 in disulfidptosis |
| Autophagy-related genes (ATG) | Autophagosome formation | Downstream of Ulk1 activation |
| AMPK substrates | Metabolic enzymes and transcription factors | Broad rewiring under glucose starvation [1,8] |
| mTORC1 components | Nutrient sensing | Inhibited by glucose limitation |
| Beta-hydroxybutyrate-producing enzymes | Ketone body metabolism | Link to histone modification |
| Mitochondrial metabolic enzymes | Energy production | Involved in ferroptosis modulation |
| Stress kinases | Stress signaling | Activated by glucose deprivation [6,7] |
How Is cellular response to glucose starvation Regulated?
The cellular response to glucose starvation is regulated primarily through the AMPK-mTOR axis. Glucose deprivation activates AMPK, which phosphorylates Ulk1 to promote autophagy, while simultaneously inhibiting mTOR, removing its suppressive phosphorylation of Ulk1. This reciprocal regulation ensures that autophagy is rapidly induced when energy is low. Downstream, transcription factors such as FoxO3 mediate energy stress responses that can modulate ferroptosis. Epigenetic regulation via histone beta-hydroxybutyrylation provides a slower, transcriptional layer of control. Additionally, ER stress pathways and SLC7A11-dependent redox regulation influence cell fate under glucose limitation. FicD-mediated AMPylation adds another regulatory node that tunes sensitivity to glucose fluctuations.
cellular response to glucose starvation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC7A11 | Disulfidptosis in cancer | CRISPR knockout in cancer cell lines followed by glucose limitation |
| AMPK | Metabolic stress and ferroptosis | AMPK knockout or point-mutation models [1,8] |
| IDH2 | Metabolic disorders, gluconeogenesis | Liver-specific IDH2 knockout mice |
| Tau | Neurodegeneration | Fission yeast tau expression models |
| FicD | Glucose fluctuation sensitivity | FicD knockout mouse embryonic fibroblasts |
Cancer metabolism and disulfidptosis
Many cancer cells rely on glucose and are sensitive to its deprivation. Glucose limitation can induce disulfidptosis in SLC7A11-high cancer cells, and inhibiting ER stress cooperates with SLC7A11 to promote this cell death and suppress tumor growth. This makes GO:0042149 a target for metabolic anticancer strategies. AMPK/FoxO3 signaling also modulates ferroptosis, another iron-dependent cell death pathway relevant to cancer therapy.
Neurodegeneration and tau phosphorylation
Glucose starvation induces tau phosphorylation and cellular stress in fission yeast, suggesting a conserved link between metabolic stress and tau-related neurodegeneration. This supports the hypothesis that impaired glucose metabolism contributes to neurodegenerative pathologies.
Metabolic disorders and gluconeogenesis
IDH2 regulates glycolysis and gluconeogenesis, and its dysfunction may contribute to metabolic disorders where glucose homeostasis is impaired. The cellular response to glucose starvation is therefore relevant to diabetes and hepatic metabolic disease research.
Cell death and stress adaptation
Glucose deprivation triggers ER stress and can lead to disulfidptosis or ferroptosis depending on cellular context [4,8]. Understanding these decision points is important for developing therapies that selectively kill stressed cells, such as cancer cells in glucose-poor tumor regions.
From cellular response to glucose starvation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does AMPK phosphorylation of Ulk1 drive autophagy under glucose starvation? | Ulk1 point-mutation knock-in cells (phospho-deficient) |
| Is SLC7A11 required for disulfidptosis upon glucose limitation? | SLC7A11 knockout cancer cells |
| Does IDH2 regulate gluconeogenesis in vivo? | Liver-specific IDH2 knockout mice |
| How does FicD modulate sensitivity to glucose fluctuations? | FicD knockout mouse embryonic fibroblasts |
| Does tau phosphorylation mediate stress response to glucose starvation? | Tau knockout or phospho-mutant fission yeast |
| Can FoxO3 activation modulate ferroptosis under energy stress? | FoxO3 knockout or overexpression cell lines |
How to Study the cellular response to glucose starvation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Western blot | Protein phosphorylation and expression | AMPK/Ulk1/mTOR signaling |
| GFP-LC3 imaging | Autophagosome formation | Autophagy flux under glucose starvation |
| RNA-seq | Transcriptional changes | Gene expression response to glucose limitation |
| Metabolomics | Metabolite levels and flux | Metabolic rewiring and IDH2 function |
| CRISPR knockout | Gene function loss | Testing requirement of SLC7A11, AMPK, etc. [4,8] |
| Phospho-proteomics | Global phosphorylation changes | Kinase pathway mapping |
| Cell viability assays | Cell death induction | Disulfidptosis and ferroptosis studies [4,8] |
Measuring autophagy flux
Autophagy induction under glucose starvation can be monitored using LC3 lipidation assays, GFP-LC3 puncta imaging, and autophagic flux measurements with lysosomal inhibitors. These methods directly assess the Ulk1-AMPK axis output.
Phospho-signaling analysis
Western blotting with phospho-specific antibodies against AMPK, Ulk1, mTOR substrates and FoxO3 can quantify pathway activation. This is essential for confirming that glucose starvation engages the expected kinases [1,8].
Transcriptomic and epigenomic profiling
RNA-seq reveals gene expression changes, while ChIP-seq or mass spectrometry can detect histone modifications such as beta-hydroxybutyrylation. These approaches link metabolism to transcriptional and epigenetic regulation.
Metabolomics and flux analysis
Metabolite profiling and isotope tracing measure changes in glycolysis, gluconeogenesis and energy charge. This is particularly useful for studying IDH2 and central carbon metabolism.
How CRISPR Can Be Used to Study GO:0042149 cellular response to glucose starvation
Knockout
CRISPR knockout of genes such as AMPK, Ulk1, SLC7A11 or IDH2 allows researchers to test their requirement for the cellular response to glucose starvation. For example, SLC7A11 knockout abolishes disulfidptosis under glucose limitation, and AMPK knockout prevents Ulk1 phosphorylation and autophagy induction.
Point Mutation
Knock-in of phospho-deficient or phospho-mimetic mutations in Ulk1 can dissect the specific contribution of AMPK phosphorylation sites to autophagy and survival under glucose starvation. Similarly, point mutations in metabolic enzymes can reveal catalytic requirements.
Knock-in
Tagged knock-in of endogenous genes with fluorescent or affinity tags enables real-time imaging and proteomic analysis of proteins such as Ulk1 or AMPK during glucose starvation. This provides spatial and temporal resolution of the response.
Overexpression
Overexpression of wild-type or mutant forms of key regulators, such as FoxO3 or IDH2, can test sufficiency for driving metabolic or cell death outcomes under glucose limitation [5,8]. This complements loss-of-function studies.
How EDITGENE Supports cellular response to glucose starvation Research
Researchers studying cellular response to glucose starvation-related genes often need to determine whether a candidate gene is causally involved in metabolic adaptation, autophagy or cell death. EDITGENE provides CRISPR-based cell model services to enable precise functional interrogation of GO:0042149 components.
Contact EDITGENE today to design your custom CRISPR model for cellular response to glucose starvation research.
Frequently Asked Questions About cellular response to glucose starvation
What is cellular response to glucose starvation GO:0042149?
It is the biological process by which a cell changes its state or activity when deprived of glucose, including metabolic rewiring, autophagy, gene expression changes and stress responses [1,2].
What genes are involved in cellular response to glucose starvation?
Key genes include AMPK, Ulk1, mTOR, FoxO3, SLC7A11, IDH2, FicD and tau, among others [1,2,4,5,7,8].
How does AMPK regulate autophagy under glucose starvation?
AMPK directly phosphorylates Ulk1 to activate autophagy, while mTOR is inhibited, removing its suppressive phosphorylation of Ulk1.
What is disulfidptosis and how is it related to glucose starvation?
Disulfidptosis is a cell death mode triggered by glucose limitation in SLC7A11-high cells, involving disulfide stress and ER stress.
Can glucose starvation induce ferroptosis?
Yes, energy stress can modulate ferroptosis through AMPK/FoxO3 signaling.
What experimental models are used to study glucose starvation response?
Common models include CRISPR knockout cell lines, phospho-mutant knock-ins, mouse embryonic fibroblasts, fission yeast and cancer cell lines [1,2,4,7].
How is histone modification linked to glucose starvation?
Glucose starvation can increase beta-hydroxybutyrate, which modifies histones via lysine beta-hydroxybutyrylation, regulating gene expression.
What role does IDH2 play in glucose metabolism?
IDH2 regulates glycolysis and gluconeogenesis, linking mitochondrial metabolism to glucose homeostasis.
Is the glucose starvation response conserved in yeast?
Yes, fission yeast shows tau phosphorylation and stress responses upon glucose starvation, indicating conservation.
How can CRISPR screens help identify new glucose starvation genes?
Genome-wide CRISPR screens can uncover genes required for survival or death under glucose limitation, revealing novel regulators.
Conclusion
GO:0042149 cellular response to glucose starvation is a central biological process that integrates energy sensing, autophagy, metabolism, epigenetics and cell death decisions. The AMPK-mTOR-Ulk1 axis, SLC7A11-dependent disulfidptosis, IDH2-mediated metabolic control and conserved stress responses across organisms highlight its broad importance [1,2,4,5,7,8]. Understanding this process has direct implications for cancer, neurodegeneration and metabolic disease research. CRISPR-based models and multi-omics approaches are powerful tools to dissect the underlying mechanisms and identify therapeutic targets.
References
- 1. Kim J et al.. 2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.. Nat Cell Biol 13(2):132-41 PMID: 21258367
- 2. Gulen B et al.. 2024. FicD sensitizes cellular response to glucose fluctuations in mouse embryonic fibroblasts.. Proc Natl Acad Sci U S A 121(38):e2400781121 PMID: 39259589
- 3. Xie Z et al.. 2016. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation.. Mol Cell 62(2):194-206 PMID: 27105115
- 4. Wang J et al.. 2025. Inhibition of Endoplasmic Reticulum Stress Cooperates with SLC7A11 to Promote Disulfidptosis and Suppress Tumor Growth upon Glucose Limitation.. Adv Sci (Weinh) 12(7):e2408789 PMID: 39739602
- 5. Wang H et al.. 2023. Hepatic IDH2 regulates glycolysis and gluconeogenesis.. Metabolism 143:155559 PMID: 37044373
- 6. Chiodi I et al.. 2019. Cellular response to glutamine and/or glucose deprivation in in vitro transformed human fibroblasts.. Oncol Rep 41(6):3555-3564 PMID: 31002368
- 7. Yılmazer M et al.. 2025. Glucose starvation induces tau phosphorylation leading to cellular stress response in fission yeast.. Arch Microbiol 207(7):148 PMID: 40387938
- 8. Zhong S et al.. 2023. Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis.. Redox Biol 63:102760 PMID: 37267686
