TMBIM5 is the Ca(2+) /H(+) antiporter of mammalian mitochondria.
TMBIM5 is the Ca(2+) /H(+) antiporter of mammalian mitochondria.
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TMBIM5是哺乳动物线粒体的Ca（2+） /H（+）抗胞毒剂。
DOI：
10.15252/embr.202254978
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发表时间：
2022-12-06
期刊：
影响因子：
7.7
通讯作者：
中科院分区：
文献类型：
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作者：
线粒体钙离子是生物能量学和细胞死亡途径的重要调节因子。线粒体Ca~(2+)含量和细胞内Ca~(2+)稳态严格依赖于Ca~(2+)转运体。近几十年来，除了线粒体Ca~(2+)/H~+交换器(ChE)外，线粒体Ca~(2+)摄取和释放的主要调控因子已被发现。LETM1最初被鉴定为线粒体K+/H+交换器，也被认为是线粒体ChE的候选基因。通过对LETM1线粒体相互作用组的定义，我们鉴定了TMBIM家族中唯一的线粒体成员TMBIM5/MICS1，并验证了TMBIM5与LETM1的物理相互作用。基于细胞的和无细胞的生化分析表明，TMBIM5基因敲除突变体和pH敏感位点突变体分别缺乏或显著减少了线粒体Na+非依赖性的钙释放，以及重组TMBIM5对pH依赖的钙转运。综上所述，我们证明了TMBIM5，而不是LETM1，是长期寻找的线粒体ChE，参与设置和调节线粒体质子梯度。这一发现提供了线粒体钙转运体的最后一块拼图，并为探索其在健康和疾病中的重要性以及开发调节钙离子交换的药物打开了大门。TMBIM5介导线粒体Ca~(2+)/H~+交换，并与K~+/H~+交换器LETM1相互作用，维持线粒体pH、Ca~(2+)和K~+动态平衡。
Mitochondrial Ca2+ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca2+ content and cytosolic Ca2+ homeostasis strictly depend on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+/H+ exchanger (CHE). Originally identified as the mitochondrial K+/H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell‐based and cell‐free biochemical assays demonstrate the absence or greatly reduced Na+‐independent mitochondrial Ca2+ release in TMBIM5 knockout or pH‐sensing site mutants, respectively, and pH‐dependent Ca2+ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long‐sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange. TMBIM5 mediates mitochondrial Ca2+/H+ exchange and interacts with the K+/H+ exchanger LETM1 to maintain mitochondrial pH, Ca2+ and K+ homeostasis.
影响因子：
4
作者：
Nowikovsky K;Bernardi P
通讯作者：
Bernardi P