期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：35
页码：21731-21739
DOI：10.1073/pnas.2005976117
出版社：The National Academy of Sciences of the United States of America
摘要：Ca 2 uptake by mitochondria regulates bioenergetics, apoptosis, and Ca 2 signaling. The primary pathway for mitochondrial Ca 2 uptake is the mitochondrial calcium uniporter (MCU), a Ca 2 -selective ion channel in the inner mitochondrial membrane. MCU-mediated Ca 2 uptake is driven by the sizable inner-membrane potential generated by the electron-transport chain. Despite the large thermodynamic driving force, mitochondrial Ca 2 uptake is tightly regulated to maintain low matrix [Ca 2 ] and prevent opening of the permeability transition pore and cell death, while meeting dynamic cellular energy demands. How this is accomplished is controversial. Here we define a regulatory mechanism of MCU-channel activity in which cytoplasmic Ca 2 regulation of intermembrane space-localized MICU1/2 is controlled by Ca 2 -regulatory mechanisms localized across the membrane in the mitochondrial matrix. Ca 2 that permeates through the channel pore regulates Ca 2 affinities of coupled inhibitory and activating sensors in the matrix. Ca 2 binding to the inhibitory sensor within the MCU amino terminus closes the channel despite Ca 2 binding to MICU1/2. Conversely, disruption of the interaction of MICU1/2 with the MCU complex disables matrix Ca 2 regulation of channel activity. Our results demonstrate how Ca 2 influx into mitochondria is tuned by coupled Ca 2 -regulatory mechanisms on both sides of the inner mitochondrial membrane.
