title: Mitochondrial calcium uptake.
abstract: Calcium (Ca(2+)) uptake into the mitochondrial matrix is critically important to cellular function. As a regulator of matrix Ca(2+) levels, this flux influences energy production and can initiate cell death. If large, this flux could potentially alter intracellular Ca(2+) ([Ca(2+)]i) signals. Despite years of study, fundamental disagreements on the extent and speed of mitochondrial Ca(2+) uptake still exist. Here, we review and quantitatively analyze mitochondrial Ca(2+) uptake fluxes from different tissues and interpret the results with respect to the recently proposed mitochondrial Ca(2+) uniporter (MCU) candidate. This quantitative analysis yields four clear results: (i) under physiological conditions, Ca(2+) influx into the mitochondria via the MCU is small relative to other cytosolic Ca(2+) extrusion pathways; (ii) single MCU conductance is ∼6-7 pS (105 mM [Ca(2+)]), and MCU flux appears to be modulated by [Ca(2+)]i, suggesting Ca(2+) regulation of MCU open probability (P(O)); (iii) in the heart, two features are clear: the number of MCU channels per mitochondrion can be calculated, and MCU probability is low under normal conditions; and (iv) in skeletal muscle and liver cells, uptake per mitochondrion varies in magnitude but total uptake per cell still appears to be modest. Based on our analysis of available quantitative data, we conclude that although Ca(2+) critically regulates mitochondrial function, the mitochondria do not act as a significant dynamic buffer of cytosolic Ca(2+) under physiological conditions. Nevertheless, with prolonged (superphysiological) elevations of [Ca(2+)]i, mitochondrial Ca(2+) uptake can increase 10- to 1,000-fold and begin to shape [Ca(2+)]i dynamics.
authors.affiliation: Center for Biomedical Engineering and Technology, and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: George S B
authors.initials: GS
authors.lastname: Williams
authors.forename: Liron
authors.initials: L
authors.lastname: Boyman
authors.forename: Aristide C
authors.initials: AC
authors.lastname: Chikando
authors.forename: Ramzi J
authors.initials: RJ
authors.lastname: Khairallah
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: NCLX; NCX; SERCA; inner mitochondrial membrane; microdomain