Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport.
Mitochondrial Ca(2+) uptake is crucial for the regulation of the rate of oxidative phosphorylation, the modulation of spatio-temporal cytosolic Ca(2+) signals and apoptosis. Although the phenomenon of mitochondrial Ca(2+) sequestration, its characteristics and physiological consequences have been convincingly reported, the actual protein(s) involved in this process are unknown. Here, we show that the uncoupling proteins 2 and 3 (UCP2 and UCP3) are essential for mitochondrial Ca(2+) uptake. Using overexpression, knockdown (small interfering RNA) and mutagenesis experiments, we demonstrate that UCP2 and UCP3 are elementary for mitochondrial Ca(2+) sequestration in response to cell stimulation under physiological conditions - observations supported by isolated liver mitochondria of Ucp2(-/-) mice lacking ruthenium red-sensitive Ca(2+) uptake. Our results reveal a novel molecular function for UCP2 and UCP3, and may provide the molecular mechanism for their reported effects. Moreover, the identification of proteins fundemental for mitochondrial Ca(2+) uptake expands our knowledge of the physiological role for mitochondrial Ca(2+) sequestration.
Trenker
Michael
M
Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
Malli
Roland
R
Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
Fertschai
Ismene
I
Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
Levak-Frank
Sanja
S
Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
Graier
Wolfgang F
WF
Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D017433:Protein Structure, Secondary; D034741:RNA, Small Interfering / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D007473:Ion Channels; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; C000604390:Ucp2 protein, mouse; C000604393:Ucp3 protein, mouse; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D002118:Calcium