Research Showcase - Zongchao Jia
The structure of the MICU1‐MICU2 complex unveils the regulation of the mitochondrial calcium uniporter
Mitochondrial Ca2+ uptake is involved in many fundamental cellular activities, such as stimulation of ATP production, regulation of cellular metabolism, and buffering of cytoplasmic Ca2+ concentration. It has been shown that mitochondrial Ca2+ uptake is mainly via uniporter channels located in the inner mitochondrial membrane with high Ca2+ affinity and selectivity. Loss or abnormal expression of uniporter subunits leads to a variety of disorders, including neurodevelopmental disorders, skeletal muscle atrophy, and learning and movement disorders, and thus intracellular calcium homeostasis is essential for the maintenance of normal life activities.
The Ca2+ uptake threshold of the unidirectional transporter is jointly regulated by the Ca2+-binding proteins MICU1 and MICU2, both of which contain two classical EF-hand Ca2+-binding domains. A collaborative research effort between Zongchao Jia and Jimin Zheng (Jia’s former PhD student) at Beijing Normal University has been focusing on Ca2+ uniporter for some time, and in 2019 they reported the three-dimensional structure of the Ca2+-bound state of MICU2 (EMBO Reports). Recently, they have successfully resolved the three-dimensional structures of the Ca2+-free and Ca2+-bound MICU1-MICU2 complexes (EMBO Journal), revealing critical transitioning process between the two states. The interaction between MICU1 and MICU2, as well as between MICU1 and the bridging protein EMRE, was identified by protein surface charge analysis and microscale thermophoresis. The electrostatic interaction between the basic pocket of MICU1 protein and the acidic C-terminus of EMRE was enhanced in the presence of Ca2+. In contrast, the MICU1-MCU (MCU is Ca2+ channel) interaction was enhanced in the absence of Ca2+. This interconversion of the MICU1-MCU and MICU1-EMRE interactions facilitates Ca2+ signal its transmission from the regulatory subunits to the ion channel, thus uncovering the two opposing functional switching mechanisms, namely "gating" and "synergistic activation” by MICU1-MICU2 complex. Finally, the exogenous EMRE C-terminal peptide was shown to compete with the intracellular source of EMRE. The peptide lowered the threshold of MCU calcium uptake in the resting state while increased the accumulation of Ca2+ under stimulation in the mitochondria. Taken together, this work has shed new lights on how MICU1-MICU2, together with EMRE, collectively regulate mitochondrial Ca2+ uptake.