Biphasic Regulation of Mitochondrial Ca2+ Uptake by Cytosolic Ca2+ Concentration

SummaryA rise in cytosolic Ca2+ concentration is used as a key activation signal in virtually all animal cells, where it triggers a range of responses including neurotransmitter release, muscle contraction, and cell growth and proliferation [1]. During intracellular Ca2+ signaling, mitochondria rapidly take up significant amounts of Ca2+ from the cytosol, and this stimulates energy production, alters the spatial and temporal profile of the intracellular Ca2+ signal, and triggers cell death 2, 3, 4, 5, 6, 7, 8, 9 and 10. Mitochondrial Ca2+ uptake occurs via a ruthenium-red-sensitive uniporter channel found in the inner membrane [11]. In spite of its critical importance, little is known about how the uniporter is regulated. Here, we report that the mitochondrial Ca2+ uniporter is gated by cytosolic Ca2+. Ca2+ uptake into mitochondria is a Ca2+-activated process with a requirement for functional calmodulin. However, cytosolic Ca2+ subsequently inactivates the uniporter, preventing further Ca2+ uptake. The uptake pathway and the inactivation process have relatively low Ca2+ affinities of approximately 10–20 μM. However, numerous mitochondria are within 20–100 nm of the endoplasmic reticulum, thereby enabling rapid and efficient transmission of Ca2+ release into adjacent mitochondria by InsP3 receptors on the endoplasmic reticulum. Hence, biphasic control of mitochondrial Ca2+ uptake by Ca2+ provides a novel basis for complex physiological patterns of intracellular Ca2+ signaling.