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<p>The bidirectional transport of Ca<sup>2+</sup> into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca<sup>2+</sup> efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na<sup>+</sup>/Ca<sup>2+</sup> exchanger. Its downregulation chronically elevates basal [Ca²⁺]<sub>mt</sub> and impairs efflux upon stimulation. In <i>Caenorhabditis elegans</i>, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca<sup>2+</sup> accumulation critically contribute to degenerative pathways.</p>

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TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Massimo Vetralla,
  • Lena Wischhof,
  • Asrat Kahsay,
  • Vanessa Cadenelli,
  • Enzo Scifo,
  • Beijia Xie,
  • Miriana Sbrissa,
  • Maëlle Sandhira Habert,
  • Dan Ehninger,
  • Rosario Rizzuto,
  • Daniele Bano,
  • Diego De Stefani

摘要

The bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.