Mitochondrial Calcium Uniporter in Signaling and Dynamics

线粒体Ca 2+摄取控制许多细胞功能，包括能量代谢、信号传导和动力学。线粒体Ca 2+蓄积由高度负性的线粒体内膜电位的强大驱动力支持，但仅在胞质[Ca 2 +]升高时的Ca 2+信号期间被激活。Ca 2+信号通过通道（钙单向转运体（mtCU））传播到线粒体基质，所述通道由成孔MCU、支架EMRE和MICU 1与自身、MICU 2或MICU 3的Ca 2+传感调节二聚体组成。MICU 1缺失导致mtCU永久开放，而MICU 2缺失增加，MICU 3缺失降低了mtCU门控的Ca 2+敏感性。我们和其他人已经证明MICU 1缺失会导致小鼠的围产期死亡，MICU 1和MICU 2突变都与人类疾病有关。证据也开始积累，支持MICU 1在常见疾病如缺血-再灌注和癌症中的降低。然而，尽管MICU广泛的疾病相关性，它们对钙信号传导和细胞器、细胞和组织结构和功能的组织的贡献仍然不确定。在这里，我们提出了初步的数据表明细胞与细胞和细胞内的异质性在MICU，这可能是相关的细胞在复杂的器官的专业化。MICU 1损失被证明是其次是次要的mtCU组成的变化，这可能是适应性或适应不良，但这些变化的时间顺序和其他超出mtCU本身是未知的。而MICU 1损失诱导的细胞损伤已被归因于线粒体Ca 2+超载，我们的初步研究结果指出其他贡献者的重要性，即线粒体活性氧和结构改变。因此，阐明MICU促进Ca 2+信号传导的细胞内和细胞间组织以及线粒体结构和功能稳定性的机制具有重要意义。在这里，我们提出的假设，MICUs是重要的个别细胞的Ca 2+信号指纹，氧化还原稳态和融合裂变和嵴动态的线粒体。为了测试这些想法，我们开发了新的检测方法，并组装了一系列细胞和小鼠遗传模型。我们的具体目标是确定（1）MTCU的MICU 1门控是否在Ca 2+信号传导中产生细胞内异质性;（2）MICU对MTCU门控的控制是否与线粒体氧化还原稳态相关;（3）MICU 1、MICU 2和MICU 3是否有助于控制线粒体融合-裂变动力学和嵴成形，这些贡献取决于MTCU的门控。这些目标的完成将提供线索的机制，MICUs支持线粒体膜动力学和信号转导和发病机制的干扰mtCU的结构和功能。

Mitochondrial Ca2+ uptake controls many cell functions, including energy metabolism, signaling and dynamics. Mitochondrial Ca2+ accumulation is supported by the robust driving force of the highly negative, inner mitochondrial membrane potential, but is activated only during Ca2+ signals, when cytoplasmic [Ca2+] is elevated. Ca2+ signals are propagated to the mitochondrial matrix through a channel, the calcium uniporter (mtCU), comprised of pore-forming MCU, scaffold EMRE, and Ca2+-sensing regulatory dimers of MICU1 with itself, MICU2 or MICU3. MICU1 deletion results in a permanently open mtCU, whereas MICU2 loss increases and MICU3 loss decreases the Ca2+ sensitivity of the mtCU gating. MICU1 deletion has been shown by us and others to cause perinatal death in mouse and both MICU1 and MICU2 mutations have been linked to human diseases. Evidence has also started to accumulate in support of MICU1 decrease in common disorders like ischemia-reperfusion and cancer. However, despite the MICUs broad disease relevance, their contribution to the organization of calcium signaling and organelle, cell and tissue structure and functions remains undetermined. Here we present preliminary data indicating cell-to-cell and intracellular heterogeneity in the MICUs, which might be relevant for specialization of cells in complex organs. MICU1 loss was shown to be followed by secondary mtCU composition changes, which might be either adaptive or maladaptive, however the temporal ordering of these changes and others beyond the mtCU itself are not known. Whereas MICU1 loss-induced cell injury has been attributed to mitochondrial Ca2+ overload, our preliminary findings point to the importance of other contributors, namely mitochondrial reactive oxygen species and structural alterations. Thus, delineating the mechanisms by which MICUs contribute to the inter-and intracellular organization of Ca2+ signaling and the stability of mitochondrial structure and function are of vast significance. Here we pose the hypothesis that MICUs are important for individual cells’ Ca2+ signal fingerprints, for redox homeostasis and for fusion-fission and cristae dynamics of the mitochondria. To test these ideas, we have developed novel assays and assembled an array of cell and mouse genetic models. Our specific aims are to determine (1) if MICU1 gating of the mtCU creates intracellular heterogeneity in Ca2+ signaling; (2) if the control of mtCU gating by MICUs is relevant for mitochondrial redox homeostasis; (3) if MICU1, MICU2 and MICU3 contribute to the control of mitochondrial fusion-fission dynamics and cristae shaping and these contributions depend on the gating of the mtCU. Completion of these aims will provide clues to the mechanisms by which MICUs support mitochondrial membrane dynamics and signaling and to the pathogenesis initiated by perturbing mtCU structure and function.