The mitochondrial calcium uniporter is a highly selective ion channel.
During intracellular Ca2+ signalling mitochondria accumulate significant amounts of Ca2+ from the cytosol. Mitochondrial Ca2+ uptake controls the rate of energy production, shapes the amplitude and spatio-temporal patterns of intracellular Ca2+ signals, and is instrumental to cell death. This Ca2+ uptake is undertaken by the mitochondrial Ca2+ uniporter (MCU) located in the organelle's inner membrane. The uniporter passes Ca2+ down the electrochemical gradient maintained across this membrane without direct coupling to ATP hydrolysis or transport of other ions. Carriers are characterized by turnover numbers that are typically 1,000-fold lower than ion channels, and until now it has been unclear whether the MCU is a carrier or a channel. By patch-clamping the inner mitochondrial membrane, we identified a previously unknown Ca2+-selective ion channel sensitive to inhibitors of mitochondrial Ca2+ uptake. Our data indicate that this unique channel binds Ca2+ with extremely high affinity (dissociation constant < or =2 nM), enabling high Ca2+ selectivity despite relatively low cytoplasmic Ca2+ concentrations. The channel is inwardly rectifying, making it especially effective for Ca2+ uptake into energized mitochondria. Thus, we conclude that the properties of the current mediated by this novel channel are those of the MCU.
Kirichok
Yuriy
Y
Howard Hughes Medical Institute, Department of Cardiovascular Research, Children's Hospital, andHarvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA.
Krapivinsky
Grigory
G
Clapham
David E
DE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004553:Electric Conductivity; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017975:Ruthenium Compounds / Q000494:pharmacology
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D002413:Cations, Divalent; D024101:Mitochondrial Proteins; C112020:Ru 360; D017975:Ruthenium Compounds; C034703:mitochondrial calcium uniporter; D000255:Adenosine Triphosphate; D002118:Calcium