Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster
Objectives: The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. Th...
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| Format: | Article |
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Elsevier
2025-03-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000134 |
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| author | Yasaman Heidarian Tess D. Fasteen Liam Mungcal Kasun Buddika Nader H. Mahmoudzadeh Travis Nemkov Angelo D'Alessandro Jason M. Tennessen |
| author_facet | Yasaman Heidarian Tess D. Fasteen Liam Mungcal Kasun Buddika Nader H. Mahmoudzadeh Travis Nemkov Angelo D'Alessandro Jason M. Tennessen |
| author_sort | Yasaman Heidarian |
| collection | DOAJ |
| description | Objectives: The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we examine the possibility that the Drosophila ortholog of Hypoxia inducible factor 1α (Hif1α) is also required to activate the larval glycolytic program. Methods: CRISPR/Cas9 was used to generate new loss-of-function alleles in the Drosophila gene similar (sima), which encodes the sole fly ortholog of Hif1α. The resulting mutant strains were analyzed using a combination of metabolomics and RNAseq for defects in carbohydrate metabolism. Results: Our studies reveal that sima mutants fail to activate aerobic glycolysis and die during larval development with metabolic phenotypes that mimic those displayed by dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein. Conclusions: These findings demonstrate that Sima/HIF1α is required during embryogenesis to coordinately up-regulate carbohydrate metabolism in preparation for larval growth. Notably, our study also reveals that the Sima/HIF1α-dependent gene expression program shares considerable overlap with that observed in dERR mutant, suggesting that Sima/HIF1α and dERR cooperatively regulate embryonic and larval glycolytic gene expression. |
| format | Article |
| id | doaj-art-ede7c1354d244deca187d2196e14f880 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-ede7c1354d244deca187d2196e14f8802025-02-12T05:31:03ZengElsevierMolecular Metabolism2212-87782025-03-0193102106Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogasterYasaman Heidarian0Tess D. Fasteen1Liam Mungcal2Kasun Buddika3Nader H. Mahmoudzadeh4Travis Nemkov5Angelo D'Alessandro6Jason M. Tennessen7Department of Biology, Indiana University, Bloomington, IN 47405, USADepartment of Biology, Indiana University, Bloomington, IN 47405, USADepartment of Biology, Indiana University, Bloomington, IN 47405, USADepartment of Biology, Indiana University, Bloomington, IN 47405, USADepartment of Biology, Indiana University, Bloomington, IN 47405, USADepartment of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USADepartment of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USADepartment of Biology, Indiana University, Bloomington, IN 47405, USA; Member, Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA; Corresponding author. Department of Biology, Indiana University, Bloomington, IN 47405, USA.Objectives: The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we examine the possibility that the Drosophila ortholog of Hypoxia inducible factor 1α (Hif1α) is also required to activate the larval glycolytic program. Methods: CRISPR/Cas9 was used to generate new loss-of-function alleles in the Drosophila gene similar (sima), which encodes the sole fly ortholog of Hif1α. The resulting mutant strains were analyzed using a combination of metabolomics and RNAseq for defects in carbohydrate metabolism. Results: Our studies reveal that sima mutants fail to activate aerobic glycolysis and die during larval development with metabolic phenotypes that mimic those displayed by dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein. Conclusions: These findings demonstrate that Sima/HIF1α is required during embryogenesis to coordinately up-regulate carbohydrate metabolism in preparation for larval growth. Notably, our study also reveals that the Sima/HIF1α-dependent gene expression program shares considerable overlap with that observed in dERR mutant, suggesting that Sima/HIF1α and dERR cooperatively regulate embryonic and larval glycolytic gene expression.http://www.sciencedirect.com/science/article/pii/S2212877825000134Drosophila melanogasterHypoxia-inducible factor 1αEstrogen-Related ReceptorGlycolysisWarburg effect |
| spellingShingle | Yasaman Heidarian Tess D. Fasteen Liam Mungcal Kasun Buddika Nader H. Mahmoudzadeh Travis Nemkov Angelo D'Alessandro Jason M. Tennessen Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster Molecular Metabolism Drosophila melanogaster Hypoxia-inducible factor 1α Estrogen-Related Receptor Glycolysis Warburg effect |
| title | Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster |
| title_full | Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster |
| title_fullStr | Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster |
| title_full_unstemmed | Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster |
| title_short | Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster |
| title_sort | hypoxia inducible factor 1α is required to establish the larval glycolytic program in drosophila melanogaster |
| topic | Drosophila melanogaster Hypoxia-inducible factor 1α Estrogen-Related Receptor Glycolysis Warburg effect |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000134 |
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