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<p><i>MCU</i>, originally known as <i>CCDC109A</i>, is widely recognized as the gene responsible for encoding a pore-forming subunit of a Ca<sup>2+</sup>-selective channel, mitochondrial Ca<sup>2+</sup> uniporter complex (mtCUC). While MCU expression is typically highly mitochondrial-specific, we report here a protein variant derived from the <i>MCU</i> gene, termed MCU-S, which lacks the mitochondria-targeting sequence (MTS)&#xa0;and forms a Ca<sup>2+</sup>-permeable channel outside of mitochondria. The mRNA of <i>MCU-S</i> was ubiquitously expressed in all cell types/tissues tested, with particularly high expression in human platelets. MCU-S protein formed Ca<sup>2+</sup> channels at the plasma membrane, which exhibited similar channel properties to those observed in mtCUC. MCU-S channels at the plasma membrane served as an additional Ca<sup>2+</sup> influx pathway for platelet activation. Our findings show that the MCU-S functions are completely distinct from the originally reported functions of the <i>MCU</i> gene and provide additional insights into the molecular importance of MCU variant-dependent cellular Ca<sup>2+</sup> handling.</p><p></p>

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Mitochondrial Ca2+ uniporter (MCU) variants form plasma-membrane channels

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Iuliia Polina,
  • Jyotsna Mishra,
  • Michael W. Cypress,
  • Maria Landherr,
  • Nedyalka Valkov,
  • Isabel Chaput,
  • Bridget Nieto,
  • Brian Rhee,
  • Ameneh Ahrari,
  • Nathan DeMichaelis,
  • Kye-Im Jeon,
  • Ulrike Mende,
  • Peng Zhang,
  • Bong Sook Jhun,
  • Jin O-Uchi

摘要

MCU, originally known as CCDC109A, is widely recognized as the gene responsible for encoding a pore-forming subunit of a Ca2+-selective channel, mitochondrial Ca2+ uniporter complex (mtCUC). While MCU expression is typically highly mitochondrial-specific, we report here a protein variant derived from the MCU gene, termed MCU-S, which lacks the mitochondria-targeting sequence (MTS) and forms a Ca2+-permeable channel outside of mitochondria. The mRNA of MCU-S was ubiquitously expressed in all cell types/tissues tested, with particularly high expression in human platelets. MCU-S protein formed Ca2+ channels at the plasma membrane, which exhibited similar channel properties to those observed in mtCUC. MCU-S channels at the plasma membrane served as an additional Ca2+ influx pathway for platelet activation. Our findings show that the MCU-S functions are completely distinct from the originally reported functions of the MCU gene and provide additional insights into the molecular importance of MCU variant-dependent cellular Ca2+ handling.