Department of Pathology and Genomic Medicine, MitoCare Center, Thomas Jefferson University, Philadelphia, PA 19107.
Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226.
Proc Natl Acad Sci U S A. 2024 Aug 27;121(35):e2402491121. doi: 10.1073/pnas.2402491121. Epub 2024 Aug 20.
Activating Ca-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
在防止导致线粒体和细胞损伤的钙超载的同时，激活氧化代谢的钙敏感酶需要对线粒体钙摄取进行动态控制。这是通过线粒体钙摄取（MICU）1/2 蛋白来实现的，这些蛋白控制着线粒体钙单向转运体（mtCU）的孔。MICU1 在心脏中的含量相对较少，最近的研究声称哺乳动物心脏缺乏 MICU1 对 mtCU 的门控作用。然而，尚未对遗传模型进行测试。我们发现 MICU1 与人心脏中未衰竭的 MCU 存在复合物。此外，使用鼠遗传模型和药理学，我们表明 MICU1 和 MICU2 控制心脏线粒体钙内流，并且 MICU1 缺失会改变心肌细胞线粒体钙信号和能量代谢。MICU1 的缺失会导致 mtCU 组成和丰度的大量代偿性变化，早期的必需 MCU 调节剂（EMRE）和后来的 MCU 的周转率增加，这限制了线粒体钙的摄取并允许细胞存活。因此，MICU1 缺失的主要后果和随后的强大补偿都突出了 MICU1 在跳动的心脏中的相关性。
