Metabolic disruption exacerbates intestinal damage during sleep deprivation by abolishing HIF1α-mediated repair
Sleep deprivation (SD) has been reported to induce intestinal damage by several mechanisms, yet its role in modulating epithelial repair remains unclear. In this study, we find that chronic SD leads to colonic damage through continuous hypoxia. However, HIF1α, which generally responds to hypoxia to modulate barrier integrity, was paradoxically dysregulated in the colon. Further investigation revealed that a metabolic disruption during SD causes accumulation of α-ketoglutarate in the colon. The excessive α-ketoglutarate degrades HIF1α protein through PHD2 (prolyl hydroxylase 2) to abolish the intestinal repair functions of HIF1α. Collectively, these findings provide insights into how SD can exacerbate intestinal damage by fine-tuning metabolism to abolish HIF1α-mediated repair.
Authors
- Jian Ge Sun (ORCID: https://orcid.org/0000-0002-4209-7555)
- Yalin Hu (ORCID: https://orcid.org/0000-0002-0363-4362)
- Yang Luo (ORCID: https://orcid.org/0000-0001-7385-6166)
- Zi‐Jian Zheng
- Yaqing Shu (ORCID: https://orcid.org/0000-0003-1017-2554)
- Lijing Gong (ORCID: https://orcid.org/0000-0003-3502-0901)
- X. Wang (ORCID: https://orcid.org/0000-0002-8041-1592)
- Xiaoping Liao (ORCID: https://orcid.org/0000-0002-9852-910X)
- Haiyi Zhang (ORCID: https://orcid.org/0009-0008-3889-697X)
- Zhipeng Li (ORCID: https://orcid.org/0000-0001-5964-1505)
- Xiaojing Zhang (ORCID: https://orcid.org/0000-0003-1795-4399)
- Yan Li (ORCID: https://orcid.org/0000-0001-7609-2683)
- Yao Deng
- Zhihong Wu (ORCID: https://orcid.org/0000-0002-6461-412X)
- Hao Ren (ORCID: https://orcid.org/0000-0002-0094-5026)
- Wei Qiu (ORCID: https://orcid.org/0000-0003-1562-9197)
- Hongping Li (ORCID: https://orcid.org/0000-0002-3706-4791)
- Li Gong
Institutions
- South China Agricultural University (CN)
- Sun Yat-sen University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Shenzhen Children's Hospital (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-11-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114915
- Citations
- 11
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.14