Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors
- University of Miami, United States
- University of California, San Francisco, United States
- University of Calgary, Canada
Abstract
Mammalian carotid body arterial chemoreceptors function as an early warning system for hypoxia, triggering acute life-saving arousal and cardiorespiratory reflexes. To serve this role, carotid body glomus cells are highly sensitive to decreases in oxygen availability. While the mitochondria and plasma membrane signaling proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we identify HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an electron transport chain Complex IV-interacting protein that is almost exclusively expressed in the carotid body and is therefore not generally necessary for mitochondrial function. Importantly, HIGD1C is required for carotid body oxygen sensing and enhances Complex IV sensitivity to hypoxia. Thus, we propose that HIGD1C promotes exquisite oxygen sensing by the carotid body, illustrating how specialized mitochondria can be used as sentinels of metabolic stress to elicit essential adaptive behaviors.
Data availability
Data generated or analyzed during this study are included in the manuscript. Previously published RNAseq datasets were deposited in GEO under accession codes GSE72166 and GSE76579.
-
Expression profile of mouse carotid body and adrenal medullaNCBI Gene Expression Omnibus, GSE72166.
-
Single cell transcriptome analysis of mouse carotid body glomus cellsNCBI Gene Expression Omnibus, GSE76579.
Article and author information
Author details
Funding
Muscular Dystrophy Association (Career Development Award,862896)
- Alba Timón-Gómez
National Institutes of Health (UCSF Transplant T32 FAVOR Grant,P0548805)
- Alexander R Gupta
University of California, San Francisco (Physician-Scientist Scholars Program)
- James M Gardner
Canadian Institutes of Health Research (Research Grant,201603PJT/366421)
- Richard JA Wilson
Alberta Innovates - Health Solutions (Senior Scholar)
- Richard JA Wilson
National Institute of General Medical Sciences (R35 Grant,GM118141)
- Antoni Barrientos
University of California, San Francisco (Sandler Program for Breakthrough Biomedical Research,New Frontier Award)
- Andy J Chang
University of California, San Francisco (Cardiovascular Research Institute)
- Andy J Chang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments with animals were approved by the Institutional Animal Care and Use Committees at the University of California, San Francisco (AN183237-03) and the University of Calgary (AC16-0204).
Human subjects: For human tissue, CB bifurcations were procured from research-consented, de-identified organ transplant donors through a collaboration with the UCSF VITAL Core (https://surgeryresearch.ucsf.edu/laboratories-research-centers/vital-core.aspx) and designated as non-human subjects research specimens by the UCSF IRB.
Copyright
© 2022, Timón-Gómez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,669
- views
-
- 236
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors
eLife 11:e78915.
https://doi.org/10.7554/eLife.78915
Further reading
-
- Biochemistry and Chemical Biology
- Neuroscience
As the world population ages, new molecular targets in aging and Alzheimer’s disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found that neurons with the accumulation of phospho-tau immunostaining contained rG4s, rG4 structure can drive tau aggregation, and rG4 staining density depended on APOE genotype in the human tissue examined. Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation is linked to proteostasis collapse. These morphological findings suggest that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Nature has inspired the design of improved inhibitors for cancer-causing proteins.
