Uncoupling Protein 3 (UCP3) Modulates the Activity of Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) by Decreasing Mitochondrial ATP Production
| Autor: | Umberto De Marchi, Cyril Castelbou, Nicolas Demaurex |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Calcium/metabolism
SERCA Mitochondrion Biology Endoplasmic Reticulum Biochemistry Ion Channels Sarcoplasmic Reticulum Calcium-Transporting ATPases Mitochondrial Proteins 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Homeostasis Uncoupling Protein 3 Humans Uncoupling protein Calcium Signaling Gene Silencing Calcium Transport ddc:612 Uniporter Mitochondria/genetics/metabolism Molecular Biology 030304 developmental biology Calcium signaling UCP3 0303 health sciences Endoplasmic reticulum Mitochondrial Proteins/genetics/metabolism Homeostasis/physiology Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism Cell Biology Calcium Imaging Mitochondria Cell biology ATP Mitochondrial Calcium Uniporter Calcium ATPase Uncoupling Proteins Adenosine Triphosphate/biosynthesis/genetics Calcium Endoplasmic Reticulum/genetics/metabolism Ion Channels/genetics/metabolism 030217 neurology & neurosurgery Signal Transduction HeLa Cells |
| Zdroj: | Journal of Biological Chemistry, Vol. 286, No 37 (2011) pp. 32533-41 The Journal of Biological Chemistry The Journal of biological chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.216044 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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