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

Jing Yong | Helmut Bischof | Sandra Burgstaller | Marina Siirin | Anne Murphy | Roland Malli | Randal J Kaufman
eLife | 2019

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.

Pubmed ID: 31498082

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: R37DK042394
  • Agency: NCI NIH HHS, United States
    Id: P30CA030199
  • Agency: NIDDK NIH HHS, United States
    Id: R24 DK110973
  • Agency: NIDDK NIH HHS, United States
    Id: R37 DK042394
  • Agency: NCI NIH HHS, United States
    Id: P30 CA030199
  • Agency: NIA NIH HHS, United States
    Id: R01AG062190
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL052173
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK113171
  • Agency: Austrian Science Fund, International
    Id: P28529-B27
  • Agency: NIDDK NIH HHS, United States
    Id: R01DK113171
  • Agency: NCI NIH HHS, United States
    Id: R01 CA198103
  • Agency: Austrian Science Fund FWF, Austria
    Id: P 28529
  • Agency: NIA NIH HHS, United States
    Id: R01 AG062190
  • Agency: NIDDK NIH HHS, United States
    Id: R24DK110973
  • Agency: NCI NIH HHS, United States
    Id: R01CA198103
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK063491
  • Agency: NHLBI NIH HHS, United States
    Id: R01HL052173
  • Agency: NIDDK NIH HHS, United States
    Id: R01DK103185
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK103185
  • Agency: NIDDK NIH HHS, United States
    Id: P30DK063491

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