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
-
- 1,549
- views
-
- 221
- downloads
-
- 8
- 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
Senescent cells are characterized by multiple features such as increased expression of senescence-associated β-galactosidase activity (SA β-gal) and cell cycle inhibitors such as p21 or p16. They accumulate with tissue damage and dysregulate tissue homeostasis. In the context of skeletal muscle, it is known that agents used for chemotherapy such as Doxorubicin (Doxo) cause buildup of senescent cells, leading to the inhibition of tissue regeneration. Senescent cells influence the neighboring cells via numerous secreted factors which form the senescence-associated secreted phenotype (SASP). Lipids are emerging as a key component of SASP that can control tissue homeostasis. Arachidonic acid-derived lipids have been shown to accumulate within senescent cells, specifically 15d-PGJ2, which is an electrophilic lipid produced by the non-enzymatic dehydration of the prostaglandin PGD2. This study shows that 15d-PGJ2 is also released by Doxo-induced senescent cells as an SASP factor. Treatment of skeletal muscle myoblasts with the conditioned medium from these senescent cells inhibits myoblast fusion during differentiation. Inhibition of L-PTGDS, the enzyme that synthesizes PGD2, diminishes the release of 15d-PGJ2 by senescent cells and restores muscle differentiation. We further show that this lipid post-translationally modifies Cys184 of HRas in C2C12 mouse skeletal myoblasts, causing a reduction in the localization of HRas to the Golgi, increased HRas binding to Ras Binding Domain (RBD) of RAF Kinase (RAF-RBD), and activation of cellular Mitogen Activated Protein (MAP) kinase–Extracellular Signal Regulated Kinase (Erk) signaling (but not the Akt signaling). Mutating C184 of HRas prevents the ability of 15d-PGJ2 to inhibit the differentiation of muscle cells and control the activity of HRas. This work shows that 15d-PGJ2 released from senescent cells could be targeted to restore muscle homeostasis after chemotherapy.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane.
