Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+

  1. Jing Yong
  2. Helmut Bischof
  3. Sandra Burgstaller
  4. Marina Siirin
  5. Anne Murphy
  6. Roland Malli
  7. Randal J Kaufman  Is a corresponding author
  1. SBP Medical Discovery Institute, United States
  2. Medical University of Graz, Austria
  3. University of California, San Diego, United States

Abstract

The endoplasmic reticulum (ER) imports ATP and uses energy from ATP hydrolysis for protein folding and trafficking. However, little is known about how this vital ATP transport occurs across the ER membrane. Here, using three commonly used cell lines (CHO, INS1 and HeLa), we report that ATP enters the ER lumen through a cytosolic Ca2+-antagonized mechanism, or CaATiER (Ca2+-Antagonized Transport into ER). Significantly, we show that mitochondria supply ATP to the ER and a SERCA-dependent Ca2+ gradient across the ER membrane is necessary for ATP transport into the ER, through SLC35B1/AXER. We propose that under physiological conditions, increases in cytosolic Ca2+ inhibit ATP import into the ER lumen to limit ER ATP consumption. Furthermore, the ATP level in the ER is readily depleted by oxidative phosphorylation (OxPhos) inhibitors and that ER protein misfolding increases ATP uptake from mitochondria into the ER. These findings suggest that ATP usage in the ER may increase mitochondrial OxPhos while decreasing glycolysis, i.e., an 'anti-Warburg' effect.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Requests for reagents should be directed to and will be fulfilled by the Lead Contact, Randal J. Kaufman (rkaufman@sbpdiscovery.org).

Article and author information

Author details

  1. Jing Yong

    Degenerative Diseases Program, SBP Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4970-408X
  2. Helmut Bischof

    Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
  3. Sandra Burgstaller

    Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
  4. Marina Siirin

    Degenerative Diseases Program, SBP Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Anne Murphy

    Department of Pharmacology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Roland Malli

    Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6327-8729
  7. Randal J Kaufman

    Degenerative Diseases Program, SBP Medical Discovery Institute, La Jolla, United States
    For correspondence
    rkaufman@sbpdiscovery.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4277-316X

Funding

National Heart, Lung, and Blood Institute (R01HL052173)

  • Randal J Kaufman

National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)

  • Randal J Kaufman

National Institute of Diabetes and Digestive and Kidney Diseases (R37DK042394)

  • Randal J Kaufman

National Institute of Diabetes and Digestive and Kidney Diseases (R24DK110973)

  • Randal J Kaufman

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103185)

  • Randal J Kaufman

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113171)

  • Randal J Kaufman

National Institute on Aging (R01AG062190)

  • Randal J Kaufman

National Cancer Institute (R01CA198103)

  • Randal J Kaufman

National Cancer Institute (P30CA030199)

  • Randal J Kaufman

Austrian Science Fund (P28529-B27)

  • Roland Malli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nahum Sonenberg, McGill University, Canada

Version history

  1. Received: June 26, 2019
  2. Accepted: September 9, 2019
  3. Accepted Manuscript published: September 9, 2019 (version 1)
  4. Version of Record published: September 26, 2019 (version 2)

Copyright

© 2019, Yong 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. Jing Yong
  2. Helmut Bischof
  3. Sandra Burgstaller
  4. Marina Siirin
  5. Anne Murphy
  6. Roland Malli
  7. Randal J Kaufman
(2019)
Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+
eLife 8:e49682.
https://doi.org/10.7554/eLife.49682

Share this article

https://doi.org/10.7554/eLife.49682

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