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- Title
A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.
- Authors
De Stefani, Diego; Raffaello, Anna; Teardo, Enrico; Szabò, Ildikò; Rizzuto, Rosario
- Abstract
Mitochondrial Ca2+ homeostasis has a key role in the regulation of aerobic metabolism and cell survival, but the molecular identity of the Ca2+ channel, the mitochondrial calcium uniporter, is still unknown. Here we have identified in silico a protein (named MCU) that shares tissue distribution with MICU1 (also known as CBARA1), a recently characterized uniporter regulator, is present in organisms in which mitochondrial Ca2+ uptake was demonstrated and whose sequence includes two transmembrane domains. Short interfering RNA (siRNA) silencing of MCU in HeLa cells markedly reduced mitochondrial Ca2+ uptake. MCU overexpression doubled the matrix Ca2+ concentration increase evoked by inositol 1,4,5-trisphosphate-generating agonists, thus significantly buffering the cytosolic elevation. The purified MCU protein showed 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 matrix Ca2+ concentration transients when overexpressed in HeLa cells. Overall, these data demonstrate that the 40-kDa protein identified is the channel responsible for ruthenium-red-sensitive mitochondrial Ca2+ uptake, thus providing a molecular basis for this process of utmost physiological and pathological relevance.
- Subjects
MITOCHONDRIA; HOMEOSTASIS; ELECTROPHYSIOLOGY; MEMBRANE proteins; HELA cells
- Publication
Nature, 2011, Vol 476, Issue 7360, p336
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature10230