Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+
- SBP Medical Discovery Institute, United States
- Medical University of Graz, Austria
- 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).
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Author details
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.
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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Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+
eLife 8:e49682.
https://doi.org/10.7554/eLife.49682
