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Acta Physiologica 2011; Volume 203, Supplement 688
The 62nd National Congress of the Italian Physiological Society
9/25/2011-9/27/2011
Sorrento, Italy
ROLE OF MITOCHONDRIAL CALCIUM UPTAKE IN THE REGULATION OF CELL METABOLISM AND DEATH
Abstract number: O38
MAMMUCARI1 C, DE STEFANI1 D, RAFFAELLO1 A, TEARDO1 E, SZABO1 I, RIZZUTO1 R
1Dept Biomedical Sciences, Univ. of Padua, Padua, Italy
Mitochondrial Ca2+ homeostasis plays a key role in the regulation of aerobic metabolism and cell survival, but the molecular identity of the Ca2+ channel, the mitochondrial calcium uniporter, was still unknown. We have identified in silico a protein (denominated MCU) that shares tissue distribution with MICU1, a recently characterized uniporter regulator, coexists with uniporter activity in phylogeny and includes two trasmembrane domains in the sequence. siRNA silencing of MCU in HeLa cells drastically reduced mitochondrial Ca2+ uptake. MCU overexpression doubled the [Ca2+]mt rise evoked by IP3-generating agonists, thus significantly buffering the cytosolic elevation. The purified MCU protein exhibited channel activity in planar lipid bilayers, with electrophysiological properties and inhibitor sensitivity of the uniporter. A mutant MCU, in which two negatively-charged residues of the putative pore forming region were replaced, had no channel activity and reduced agonist-dependent [Ca2+]mt transients when overexpressed in HeLa cells. Overall, these data demonstrate that the identified 40 kDa protein is the channel responsible for Ruthenium Red-sensitive mitochondrial Ca2+ uptake, thus providing molecular basis for this process of utmost physiological and pathological relevance.
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Acta Physiologica 2011; Volume 203, Supplement 688 :O38