线粒体镁离子是线粒体钙单向转运体（MCU）介导的线粒体钙摄取的阳离子变阻器。

Mitochondrial Magnesium is the cationic rheostat for MCU-mediated mitochondrial Ca uptake.

作者信息

Ponnusamy Thiruvelselvan, Velusamy Prema, Kumar Amrendra, Morris Daniel, Zhang Xueqian, Ning Gang, Klinger Marianne, Copper Jean E, Rajan Sudarsan, Cheung Joseph Y, Natarajaseenivasan Kalimuthusamy, Mnatsakanyan Nelli, Shanmughapriya Santhanam

机构信息

Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.

Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.

出版信息

Res Sq. 2023 Jul 18:rs.3.rs-3088175. doi: 10.21203/rs.3.rs-3088175/v1.

DOI:10.21203/rs.3.rs-3088175/v1

PMID:37502932

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10371168/

Abstract

Calcium (Ca) uptake by mitochondria is essential in regulating bioenergetics, cell death, and cytosolic Ca transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca uptake. MCU is a heterooligomeric complex with a pore-forming component and accessory proteins required for channel activity. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here we set out to understand the mitochondrial matrix Mg-dependent regulation of MCU activity. We showed Mrs2 as the authentic mammalian mitochondrial Mg channel using the planar lipid bilayer recordings. Using a liver-specific Mrs2 KO mouse model, we showed that decreased matrix [Mg] is associated with increased MCU activity and matrix Ca overload. The disruption of Mgdependent MCU regulation significantly prompted mitochondrial permeability transition pore opening-mediated cell death during tissue IR injury. Our findings support a critical role for mMg in regulating MCU activity and attenuating mCa overload.

摘要

线粒体对钙（Ca）的摄取在调节生物能量学、细胞死亡和细胞质钙瞬变方面至关重要。线粒体钙单向转运体（MCU）介导线粒体对钙的摄取。MCU是一种异源寡聚复合物，具有形成孔道的成分和通道活性所需的辅助蛋白。尽管MCU受线粒体钙摄取蛋白（MICU）的调节已明确确立，但对于二价阳离子是否调节MCU仍需更多了解。在此，我们着手了解线粒体基质中镁对MCU活性的依赖性调节。我们通过平面脂质双层记录表明Mrs2是真正的哺乳动物线粒体镁通道。使用肝脏特异性Mrs2基因敲除小鼠模型，我们发现基质中[Mg]的降低与MCU活性增加和基质钙超载有关。镁依赖性MCU调节的破坏在组织缺血再灌注损伤期间显著促进了线粒体通透性转换孔开放介导的细胞死亡。我们的研究结果支持毫摩尔级镁在调节MCU活性和减轻线粒体钙超载方面的关键作用。