Journal
NATURE
Volume 476, Issue 7360, Pages 336-U104Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10230
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Funding
- Italian Ministry of Education, University and Research
- European Commission [223576]
- National Institutes of Health [1P01AG025532-01A1]
- Cariparo Foundation (Padua)
- Italian Association for Cancer Research (AIRC)
- Telethon-Italy [GPP1005]
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Mitochondrial Ca(2+) homeostasis has a key role in the regulation of aerobic metabolism and cell survival(1), but the molecular identity of the Ca(2+) channel, the mitochondrial calcium uniporter(2), 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(3), is present in organisms in which mitochondrial Ca(2+) uptake was demonstrated and whose sequence includes two transmembrane domains. Short interfering RNA (siRNA) silencing of MCU in HeLa cells markedly reduced mitochondrial Ca(2+) uptake. MCU overexpression doubled the matrix Ca(2+) 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 Ca(2+) 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 Ca(2+) uptake, thus providing a molecular basis for this process of utmost physiological and pathological relevance.
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