Scientific article
Open access

Uncoupling protein 3 (UCP3) modulates the activity of Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) by decreasing mitochondrial ATP production

Published inThe Journal of biological chemistry, vol. 286, no. 37, p. 32533-32541
Publication date2011

The uncoupling proteins UCP2 and UCP3 have been postulated to catalyze Ca(2+) entry across the inner membrane of mitochondria, but this proposal is disputed, and other, unrelated proteins have since been identified as the mitochondrial Ca(2+) uniporter. To clarify the role of UCPs in mitochondrial Ca(2+) handling, we down-regulated the expression of the only uncoupling protein of HeLa cells, UCP3, and measured Ca(2+) and ATP levels in the cytosol and in organelles with genetically encoded probes. UCP3 silencing did not alter mitochondrial Ca(2+) uptake in permeabilized cells. In intact cells, however, UCP3 depletion increased mitochondrial ATP production and strongly reduced the cytosolic and mitochondrial Ca(2+) elevations evoked by histamine. The reduced Ca(2+) elevations were due to inhibition of store-operated Ca(2+) entry and reduced depletion of endoplasmic reticulum (ER) Ca(2+) stores. UCP3 depletion accelerated the ER Ca(2+) refilling kinetics, indicating that the activity of sarco/endoplasmic reticulum Ca(2+) (SERCA) pumps was increased. Accordingly, SERCA inhibitors reversed the effects of UCP3 depletion on cytosolic, ER, and mitochondrial Ca(2+) responses. Our results indicate that UCP3 is not a mitochondrial Ca(2+) uniporter and that it instead negatively modulates the activity of SERCA by limiting mitochondrial ATP production. The effects of UCP3 on mitochondrial Ca(2+) thus reflect metabolic alterations that impact on cellular Ca(2+) homeostasis. The sensitivity of SERCA to mitochondrial ATP production suggests that mitochondria control the local ATP availability at ER Ca(2+) uptake and release sites.

  • Adenosine Triphosphate/biosynthesis/genetics
  • Calcium/metabolism
  • Endoplasmic Reticulum/genetics/metabolism
  • Gene Silencing
  • HeLa Cells
  • Homeostasis/physiology
  • Humans
  • Ion Channels/genetics/metabolism
  • Mitochondria/genetics/metabolism
  • Mitochondrial Proteins/genetics/metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism
Citation (ISO format)
DE MARCHI, Umberto, CASTELBOU, Cyril, DEMAUREX, Nicolas. Uncoupling protein 3 (UCP3) modulates the activity of Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) by decreasing mitochondrial ATP production. In: The Journal of biological chemistry, 2011, vol. 286, n° 37, p. 32533–32541. doi: 10.1074/jbc.M110.216044
Main files (1)
Article (Published version)
ISSN of the journal0021-9258

Technical informations

Creation06/04/2012 7:55:00 PM
First validation06/04/2012 7:55:00 PM
Update time03/14/2023 5:37:02 PM
Status update03/14/2023 5:37:02 PM
Last indexation05/02/2024 12:33:17 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack