Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors

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.

The following previously published data sets were used

Article and author information

Author details

  1. Alba Timón-Gómez

    Department of Neurology, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alexandra L Scharr

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nicholas Y Wong

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Erwin Ni

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Arijit Roy

    Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Min Liu

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Julisia Chau

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jack L Lampert

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5367-7707
  9. Homza Hireed

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Noah S Kim

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Masood Jan

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Alexander R Gupta

    Department of Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Ryan W Day

    Department of Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. James M Gardner

    Department of Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Richard JA Wilson

    Department of Physiology, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9942-4775
  16. Antoni Barrientos

    Department of Neurology, University of Miami, Miami, United States
    For correspondence
    abarrientos@med.miami.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9018-3231
  17. Andy J Chang

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Andy.Chang@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1247-4794

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

  • 1,703
    views
  • 240
    downloads
  • 10
    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)

  1. Alba Timón-Gómez
  2. Alexandra L Scharr
  3. Nicholas Y Wong
  4. Erwin Ni
  5. Arijit Roy
  6. Min Liu
  7. Julisia Chau
  8. Jack L Lampert
  9. Homza Hireed
  10. Noah S Kim
  11. Masood Jan
  12. Alexander R Gupta
  13. Ryan W Day
  14. James M Gardner
  15. Richard JA Wilson
  16. Antoni Barrientos
  17. Andy J Chang
(2022)
Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors
eLife 11:e78915.
https://doi.org/10.7554/eLife.78915

Share this article

https://doi.org/10.7554/eLife.78915

Further reading

    1. Biochemistry and Chemical Biology
    2. Computational and Systems Biology
    A Sofia F Oliveira, Fiona L Kearns ... Adrian J Mulholland
    Short Report

    The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits.

    1. Biochemistry and Chemical Biology
    2. Genetics and Genomics
    Conor J Howard, Nathan S Abell ... Nathan B Lubock
    Research Article

    Deep Mutational Scanning (DMS) is an emerging method to systematically test the functional consequences of thousands of sequence changes to a protein target in a single experiment. Because of its utility in interpreting both human variant effects and protein structure-function relationships, it holds substantial promise to improve drug discovery and clinical development. However, applications in this domain require improved experimental and analytical methods. To address this need, we report novel DMS methods to precisely and quantitatively interrogate disease-relevant mechanisms, protein-ligand interactions, and assess predicted response to drug treatment. Using these methods, we performed a DMS of the melanocortin-4 receptor (MC4R), a G-protein-coupled receptor (GPCR) implicated in obesity and an active target of drug development efforts. We assessed the effects of >6600 single amino acid substitutions on MC4R’s function across 18 distinct experimental conditions, resulting in >20 million unique measurements. From this, we identified variants that have unique effects on MC4R-mediated Gαs- and Gαq-signaling pathways, which could be used to design drugs that selectively bias MC4R’s activity. We also identified pathogenic variants that are likely amenable to a corrector therapy. Finally, we functionally characterized structural relationships that distinguish the binding of peptide versus small molecule ligands, which could guide compound optimization. Collectively, these results demonstrate that DMS is a powerful method to empower drug discovery and development.