Structural characterization of the mitochondrial Ca²⁺ uniporter provides insights into Ca²⁺ uptake and regulation

The mitochondrial uniporter is a Ca²⁺-selective ion-conducting channel in the inner mitochondrial membrane that is involved in various cellular processes. The components of this uniporter, including the pore-forming membrane subunit MCU and the modulatory subunits MCUb, EMRE, MICU1, and MICU2, have been identified in recent years. Previously, extensive studies revealed various aspects of uniporter activities and proposed multiple regulatory models of mitochondrial Ca²⁺ uptake. Recently, the individual auxiliary components of the uniporter and its holocomplex have been structurally characterized, providing the first insight into the component structures and their spatial relationship within the context of the uniporter. Here, we review recent uniporter structural studies in an attempt to establish an architectural framework, elucidating the mechanism that governs mitochondrial Ca²⁺ uptake and regulation, and to address some apparent controversies. This information could facilitate further characterization of mitochondrial Ca²⁺ permeation and a better understanding of uniporter-related disease conditions.