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

Polina, I.; Mishra, J.; Cypress, M. W.; Landherr, M.; Valkov, N.; Chaput, I.; Nieto, B.; Mende, U.; Zhang, P.; Jhun, B. S.; O-Uchi, J.

doi:10.1101/2023.07.31.551242

bioRxiv · 10.1101/2023.07.31.551242

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

Polina, I.·Mishra, J.·Cypress, M. W.·Landherr, M.·Valkov, N.·Chaput, I.·Nieto, B.·Mende, U.·Zhang, P.·Jhun, B. S.·O-Uchi, J.

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Abstract

MCU is widely recognized as a responsible gene for encoding a pore-forming subunit of highly mitochondrial-specific and Ca2+-selective channel, mitochondrial Ca2+ uniporter complex (mtCUC). Here, we report a novel short variant derived from the MCU gene (termed MCU-S) which lacks mitochondria-targeted sequence and forms a Ca2+- permeable channel outside of mitochondria. MCU-S was ubiquitously expressed in all cell-types/tissues, with particularly high expression in human platelets. MCU-S 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 finding is completely distinct from the originally reported MCU gene function and provides novel insights into the molecular basis of MCU variant-dependent cellular Ca2+ handling.

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Polina, I., Mishra, J., Cypress, M. W., Landherr, M., Valkov, N., Chaput, I., Nieto, B., Mende, U., Zhang, P., Jhun, B. S., O-Uchi, J.. 2023-08-02. Mitochondrial Ca2+ uniporter (MCU) variants form plasma-membrane channels. https://doi.org/10.1101/2023.07.31.551242

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