Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.
Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.
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DOI：
10.1016/j.celrep.2018.08.040
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发表时间：
2018-09-18
期刊：
影响因子：
8.8
通讯作者：
Csordás G
中科院分区：
文献类型：
--
作者：
De La Fuente S;Lambert JP;Nichtova Z;Fernandez Sanz C;Elrod JW;Sheu SS;Csordás G
线粒体Ca 2+升高增强ATP的产生，但摄取必须通过流出平衡，以避免过载。摄取由线粒体Ca 2+单向转运体通道复合物（MCUC）介导，而排出主要由Na+/Ca 2+交换器（NCLX）控制，两者均由内膜电位（ΔKm）电驱动。MCUC在心脏连接SR（jSR）联合处形成热点，以局部接收Ca 2+信号;然而，NCLX的分布尚不清楚。我们的分馏为基础的分析表明，广泛jSR相关的线粒体片段包含一小部分的NCLX和缺乏Na+依赖的Ca 2+的挤出。这种模式在体内NCLX过表达时保留，表明广泛靶向非jSR相关的亚线粒体结构域和功能相关性。在具有非极化MCUC分布的细胞中，在NCLX过表达时，基质Ca 2+的相同给定增加消耗更多ΔΔ μ m。因此，心脏线粒体Ca 2+摄取和排出是双极化的，可能优化跳动心脏中局部钙信号传导的能量效率。钙信号控制线粒体燃料产生。De La Fuente等人报告称，在心脏线粒体中，钙摄取和挤出在空间上是分离的;钙暴露最多的区域是摄取热点，但缺乏挤出以优化信号传导效率并最大限度地减少钙控制线粒体功能的能量消耗。
Mitochondrial Ca2+ elevations enhance ATP production, but uptake must be balanced by efflux to avoid overload. Uptake is mediated by the mitochondrial Ca2+ uniporter channel complex (MCUC), and extrusion is controlled largely by the Na+/Ca2+ exchanger (NCLX), both driven electrogenically by the inner membrane potential (Δ𝚿m). MCUC forms hotspots at the cardiac mitochondria-junctional SR (jSR) association to locally receive Ca2+ signals; however, the distribution of NCLX is unknown. Our fractionation-based assays reveal that extensively jSRassociated mitochondrial segments contain a minor portion of NCLX and lack Na+-dependent Ca2+ extrusion. This pattern is retained upon in vivo NCLX overexpression, suggesting extensive targeting to non-jSR-associated submitochondrial domains and functional relevance. In cells with non-polarized MCUC distribution, upon NCLX overexpression the same given increase in matrix Ca2+ expends more Δ𝚿m. Thus, cardiac mitochondrial Ca2+ uptake and extrusion are reciprocally polarized, likely to optimize the energy efficiency of local calcium signaling in the beating heart. Calcium signals control mitochondrial fuel generation. De La Fuente et al. report that in heart mitochondria, calcium uptake and extrusion are spatially separated; the most calcium-exposed area is an uptake hotspot, but it lacks extrusion to optimize signaling efficiency and minimize the energy expense of controlling mitochondrial function by calcium.
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