SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death.
SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death.
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DOI：
10.1091/mbc.e13-08-0502
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发表时间：
2014-03
影响因子：
3.3
通讯作者：
Madesh M
中科院分区：
文献类型：
--
作者：
Hoffman NE;Chandramoorthy HC;Shanmughapriya S;Zhang XQ;Vallem S;Doonan PJ;Malliankaraman K;Guo S;Rajan S;Elrod JW;Koch WJ;Cheung JY;Madesh M
SLC 25 A23的敲低降低线粒体Ca 2+摄取，并且SLC 25 A23与线粒体Ca 2+单向转运体的组分MCU和MICU 1相互作用。SLC 25 A23 EF-手结构域突变体的表达具有线粒体Ca 2+摄取减少的显性负性表型。它还减弱基础ROS和氧化剂诱导的ATP下降和细胞死亡。新的研究结果表明，两个谱系的线粒体Ca 2+摄取参与活动和静息状态：1）主要的真核细胞膜电位依赖性线粒体Ca 2+单向转运体和2）进化保守的交换剂和溶质载体，这也参与离子转运。虽然Ca 2+跨线粒体内膜的内流维持了代谢功能和细胞死亡信号转导，但调节线粒体Ca 2+积累的机制尚不清楚。溶质载体-溶质载体25 A23（SLC 25 A23）、SLC 25 A24和SLC 25 A25-代表一个含有EF-手的线粒体蛋白家族，其转运Mg-ATP/Pi穿过内膜。RNA干扰介导的SLC 25 A23的敲除而非SLC 25 A24和SLC 25 A25的敲除降低了组胺刺激后的线粒体Ca 2+摄取并降低了胞质Ca 2+清除。SLC 25 A23 EF-手结构域突变体的异位表达表现出线粒体Ca 2+摄取减少的显性负性表型。此外，SLC 25 A23与线粒体Ca 2+单向转运体（MCU; CCDC 109 A）和MICU 1（CBARA 1）相互作用，同时也增加IMCU。此外，SLC 25 A23敲低降低基础mROS积累，减弱氧化剂诱导的ATP下降，并减少细胞死亡。此外，与短发夹RNA不敏感的SLC 25 A23 cDNA重建恢复线粒体Ca 2+摄取和超氧化物的产生。这些结果表明SLC 25 A23在线粒体基质Ca ~（2+）内流中起重要作用。
Knockdown of SLC25A23 decreases mitochondrial Ca2+ uptake, and SLC25A23 interacts with MCU and MICU1, components of mitochondrial Ca2+ uniporter. Expression of SLC25A23 EF-hand-domain mutants has a dominant-negative phenotype of reduced mitochondrial Ca2+ uptake. It also attenuates basal ROS and oxidant-induced ATP decline and cell death. Emerging findings suggest that two lineages of mitochondrial Ca2+ uptake participate during active and resting states: 1) the major eukaryotic membrane potential–dependent mitochondrial Ca2+ uniporter and 2) the evolutionarily conserved exchangers and solute carriers, which are also involved in ion transport. Although the influx of Ca2+ across the inner mitochondrial membrane maintains metabolic functions and cell death signal transduction, the mechanisms that regulate mitochondrial Ca2+ accumulation are unclear. Solute carriers—solute carrier 25A23 (SLC25A23), SLC25A24, and SLC25A25—represent a family of EF-hand–containing mitochondrial proteins that transport Mg-ATP/Pi across the inner membrane. RNA interference–mediated knockdown of SLC25A23 but not SLC25A24 and SLC25A25 decreases mitochondrial Ca2+ uptake and reduces cytosolic Ca2+ clearance after histamine stimulation. Ectopic expression of SLC25A23 EF-hand–domain mutants exhibits a dominant-negative phenotype of reduced mitochondrial Ca2+ uptake. In addition, SLC25A23 interacts with mitochondrial Ca2+ uniporter (MCU; CCDC109A) and MICU1 (CBARA1) while also increasing IMCU. In addition, SLC25A23 knockdown lowers basal mROS accumulation, attenuates oxidant-induced ATP decline, and reduces cell death. Further, reconstitution with short hairpin RNA–insensitive SLC25A23 cDNA restores mitochondrial Ca2+ uptake and superoxide production. These findings indicate that SLC25A23 plays an important role in mitochondrial matrix Ca2+ influx.