PMID- 37603756
OWN - NLM
STAT- MEDLINE
DCOM- 20230823
LR  - 20240222
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 120
IP  - 35
DP  - 2023 Aug 29
TI  - Hypoxia induces a glycolytic complex in intestinal epithelial cells independent 
      of HIF-1-driven glycolytic gene expression.
PG  - e2208117120
LID - 10.1073/pnas.2208117120 [doi]
LID - e2208117120
AB  - The metabolic adaptation of eukaryotic cells to hypoxia involves increasing 
      dependence upon glycolytic adenosine triphosphate (ATP) production, an event with 
      consequences for cellular bioenergetics and cell fate. This response is regulated 
      at the transcriptional level by the hypoxia-inducible factor-1(HIF-1)-dependent 
      transcriptional upregulation of glycolytic enzymes (GEs) and glucose 
      transporters. However, this transcriptional upregulation alone is unlikely to 
      account fully for the levels of glycolytic ATP produced during hypoxia. Here, we 
      investigated additional mechanisms regulating glycolysis in hypoxia. We observed 
      that intestinal epithelial cells treated with inhibitors of transcription or 
      translation and human platelets (which lack nuclei and the capacity for canonical 
      transcriptional activity) maintained the capacity for hypoxia-induced glycolysis, 
      a finding which suggests the involvement of a nontranscriptional component to the 
      hypoxia-induced metabolic switch to a highly glycolytic phenotype. In our 
      investigations into potential nontranscriptional mechanisms for glycolytic 
      induction, we identified a hypoxia-sensitive formation of complexes comprising 
      GEs and glucose transporters in intestinal epithelial cells. Surprisingly, the 
      formation of such glycolytic complexes occurs independent of HIF-1-driven 
      transcription. Finally, we provide evidence for the presence of HIF-1alpha in 
      cytosolic fractions of hypoxic cells which physically interacts with the glucose 
      transporter GLUT1 and the GEs in a hypoxia-sensitive manner. In conclusion, we 
      provide insights into the nontranscriptional regulation of hypoxia-induced 
      glycolysis in intestinal epithelial cells.
FAU - Kierans, Sarah J
AU  - Kierans SJ
AUID- ORCID: 0000-0003-0691-8237
AD  - University College Dublin School of Medicine, University College Dublin, Dublin 
      D4, Ireland.
AD  - Conway Institute of Biomolecular and Biomedical Research, University College 
      Dublin, Dublin D4, Ireland.
FAU - Fagundes, Raphael R
AU  - Fagundes RR
AUID- ORCID: 0000-0003-1571-0374
AD  - Department of Gastroenterology and Hepatology, University Medical Center 
      Groningen, University of Groningen, Groningen D4, The Netherlands.
FAU - Malkov, Mykyta I
AU  - Malkov MI
AUID- ORCID: 0000-0002-7878-0890
AD  - University College Dublin School of Medicine, University College Dublin, Dublin 
      D4, Ireland.
AD  - Conway Institute of Biomolecular and Biomedical Research, University College 
      Dublin, Dublin D4, Ireland.
FAU - Sparkes, Riona
AU  - Sparkes R
AUID- ORCID: 0000-0003-2930-940X
AD  - University College Dublin School of Medicine, University College Dublin, Dublin 
      D4, Ireland.
AD  - Conway Institute of Biomolecular and Biomedical Research, University College 
      Dublin, Dublin D4, Ireland.
FAU - Dillon, Eugene T
AU  - Dillon ET
AUID- ORCID: 0000-0002-2845-3090
AD  - Conway Institute of Biomolecular and Biomedical Research, University College 
      Dublin, Dublin D4, Ireland.
FAU - Smolenski, Albert
AU  - Smolenski A
AUID- ORCID: 0000-0001-9210-9406
AD  - University College Dublin School of Medicine, University College Dublin, Dublin 
      D4, Ireland.
AD  - Conway Institute of Biomolecular and Biomedical Research, University College 
      Dublin, Dublin D4, Ireland.
FAU - Faber, Klaas Nico
AU  - Faber KN
AD  - Department of Gastroenterology and Hepatology, University Medical Center 
      Groningen, University of Groningen, Groningen D4, The Netherlands.
FAU - Taylor, Cormac T
AU  - Taylor CT
AD  - University College Dublin School of Medicine, University College Dublin, Dublin 
      D4, Ireland.
AD  - Conway Institute of Biomolecular and Biomedical Research, University College 
      Dublin, Dublin D4, Ireland.
AD  - Systems Biology Ireland, University College Dublin, Dublin D4, Ireland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230821
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Humans
MH  - *Epithelial Cells
MH  - *Glycolysis/genetics
MH  - Adenosine Triphosphate
MH  - Gene Expression
MH  - Glucose
PMC - PMC10469334
OTO - NOTNLM
OT  - HIF
OT  - glycolysis
OT  - hypoxia
OT  - metabolism
COIS- The authors declare no competing interest.
EDAT- 2023/08/21 18:42
MHDA- 2023/08/23 06:42
PMCR- 2024/02/21
CRDT- 2023/08/21 15:13
PHST- 2023/08/23 06:42 [medline]
PHST- 2023/08/21 18:42 [pubmed]
PHST- 2023/08/21 15:13 [entrez]
PHST- 2024/02/21 00:00 [pmc-release]
AID - 202208117 [pii]
AID - 10.1073/pnas.2208117120 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2023 Aug 29;120(35):e2208117120. doi: 
      10.1073/pnas.2208117120. Epub 2023 Aug 21.