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)

  • Andy J Chang

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.

Reviewing Editor

  1. David J Paterson, University of Oxford, United Kingdom

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.

Version history

  1. Preprint posted: October 5, 2021 (view preprint)
  2. Received: March 24, 2022
  3. Accepted: October 17, 2022
  4. Accepted Manuscript published: October 18, 2022 (version 1)
  5. Accepted Manuscript updated: October 20, 2022 (version 2)
  6. Version of Record published: November 4, 2022 (version 3)

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.

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  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

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