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<p>Mitochondria export Ca<sup>2+</sup> via Na<sup>+</sup>/Ca<sup>2+</sup> exchange machinery (mito-NCX) to regulate intracellular Ca<sup>2+</sup> signalling and mitochondrial Ca<sup>2+</sup> 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<sup>+</sup>/Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> dysregulation.</p>

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TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger

  • 期刊论文

  • 发表日期：

    2025年7月21日

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

摘要

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.