Journal article
The oxygen level in air directs airway epithelial cell differentiation by controlling mitochondrial citrate export
Science advances, Vol.11(4), eadr2282
01/24/2025
DOI: 10.1126/sciadv.adr2282
PMCID: PMC11759043
PMID: 39854459
Abstract
Oxygen controls most metazoan metabolism, yet in mammals, tissue O
levels vary widely. While extensive research has explored cellular responses to hypoxia, understanding how cells respond to physiologically high O
levels remains uncertain. To address this problem, we investigated respiratory epithelia as their contact with air exposes them to some of the highest O
levels in the body. We asked how the O
level in air controls differentiation of airway basal stem cells into the ciliated epithelial cells essential for clearing airborne pathogens from the lung. Through a metabolomics screen and
C tracing on primary cultures of human airway basal cells, we found that the O
level in air directs ciliated cell differentiation by increasing mitochondrial citrate export. Unexpectedly, disrupting mitochondrial citrate export elicited hypoxia transcriptional responses independently of HIF1α stabilization and at O
levels that would be hyperoxic for most tissues. These findings identify mitochondrial citrate export as a cellular mechanism for responding to physiologically high O
levels.
Details
- Title: Subtitle
- The oxygen level in air directs airway epithelial cell differentiation by controlling mitochondrial citrate export
- Creators
- Bo Ram Kim - University of IowaAdam J Rauckhorst - University of IowaMichael S Chimenti - University of IowaTayyab Rehman - University of IowaHenry L Keen - University of IowaPhilip H Karp - University of IowaEric B Taylor - University of IowaMichael J Welsh - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.11(4), eadr2282
- DOI
- 10.1126/sciadv.adr2282
- PMID
- 39854459
- PMCID
- PMC11759043
- NLM abbreviation
- Sci Adv
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Grant note
- NIH: R01 DK104998, R01 DK138664, HL091842, HL152960 University of Iowa Healthcare Distinguished Scholars Award: ADA 1- 18-PDF-060 AHA: CDA851976 Cystic Fibrosis Foundation Research Development Program
This work was supported by NIH R01 DK104998 (to E.B.T.), NIH R01 DK138664 (E.B.T.), University of Iowa Healthcare Distinguished Scholars Award (to E.B.T.), ADA 1- 18-PDF-060 (to A.J.R.), AHA CDA851976 (to A.J.R.), NIH HL091842 to (to M.J.W.), NIH HL152960 (to M.J.W.), and a Cystic Fibrosis Foundation Research Development Program (to M.J.W.). M.J.W. is an Investigator of the Howard Hughes Medical Institute. This article is subject to HHMI's Open Access to Publications policy. HHMI laboratory heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author- accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication.
- Language
- English
- Date published
- 01/24/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984775017302771
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