美国弗吉尼亚大学医学院Ming-Feng Tsai小组在研究中取得进展。他们开发出TMEM65作为线粒体Na⁺/Ca²⁺交换器发挥作用。2025年7月21日出版的《自然—细胞生物学》发表了这项成果。

课题组人员发现TMEM65耗损严重损害mito-NCX。TMEM65在心脏和大脑中高表达，但在肝脏中不表达，这与这些组织中的mito-NCX活性相关。生化和功能分析表明，TMEM65形成一种同型二聚体，含有对功能至关重要的可移动离子配位残基。TMEM65的异源表达在缺乏天然mito-NCX活性的细胞中诱导Na⁺/Ca²⁺交换。

此外，纯化的脂质体重构的TMEM65表现出mito-NCX的关键特征。该课题组人员进一步确定了CGP-37157的结合位点，CGP-37157是一种有效的、广泛靶向的mito-NCX抑制剂。最后，TMEM65缺失会提高线粒体Ca²⁺并启动线粒体向通透性转变。这些发现坚定地确立了TMEM65是介导mito-NCX的蛋白，为线粒体Ca²⁺失调相关疾病提供了新的治疗靶点。

据介绍，线粒体通过Na⁺/Ca²⁺交换机制（mito-NCX）输出Ca²⁺，调节细胞内Ca²⁺信号和线粒体Ca²⁺稳态。TMEM65最近被认为对mito-NCX至关重要，但其机制和作用尚不清楚。

附：英文原文

Title: TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger

Author: Zhang, Jim Lu, Chang, Yu-Chen, Lai, Po-Hsuan, Yeh, Han-I, Tsai, Chen-Wei, Huang, Yu-Lun, Liu, Tsung-Yun, Lee, I-Chi, Foulon, North, Xu, Yan, Rao, Bing, Shih, Hsiu-Man, Tu, Yung-Chi, Reyes, Andres V., Xu, Shou-Ling, Feng, Liang, Tsai, Ming-Feng

Issue&Volume: 2025-07-21

Abstract: Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.

DOI: 10.1038/s41556-025-01721-x

Source: https://www.nature.com/articles/s41556-025-01721-x