{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMICU2 is an essential regulatory subunit of the mitochondrial calcium uniporter (MCU) complex that forms a heterodimer with MICU1 to tightly control Ca²⁺ uptake. Biochemical and genetic studies have established that MICU2, originally identified as a paralog of MICU1 with distinct tissue‐specific expression patterns, acts predominantly as an inhibitor under resting, low‐Ca²⁺ conditions to prevent mitochondrial Ca²⁺ overload. In this role, MICU2 sets the Ca²⁺ threshold for uniporter activation while also ensuring the proper cross‐stabilization of MCU complex components in various cell types."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic and structural analyses have further revealed that MICU2 together with MICU1 binds Ca²⁺ cooperatively via their EF‐hand domains, establishing a high-affinity on–off switch that modulates uniporter activity. In response to rising cytosolic Ca²⁺ levels, conformational changes in the MICU1–MICU2 heterodimer relieve MICU2’s inhibitory action and enable rapid mitochondrial Ca²⁺ influx. Detailed crystallographic studies have delineated distinct N‑domain interfaces that determine the formation of specific MICU dimers and elucidated how Ca²⁺-dependent re-arrangement of these interfaces regulates both the threshold and gain of Ca²⁺ activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPhysiologically, MICU2 function is critical for maintaining mitochondrial Ca²⁺ homeostasis, and its deficiency has been implicated in diverse pathologies. Genetic ablation or mutations in MICU2 impair the normal threshold regulation of Ca²⁺ uptake, leading to aberrant mitochondrial Ca²⁺ accumulation that contributes to neurodevelopmental disorders, cardiomyopathies with diastolic dysfunction and vascular defects, as well as disturbances in insulin secretion. These findings underscore MICU2’s role in protecting cells and tissues by fine-tuning mitochondrial Ca²⁺ entry in response to cytosolic signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Molly Plovanich, Roman L Bogorad, Yasemin Sancak, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2014.01.013"}], "href": "https://doi.org/10.1016/j.molcel.2014.01.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24560927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24560927"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kimberli J Kamer, Zenon Grabarek, Vamsi K Mootha "}, {"type": "b", "children": [{"type": "t", "text": "High-affinity cooperative Ca"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "2+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " binding by MICU1-MICU2 serves as an on-off switch for the uniporter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.201643748"}], "href": "https://doi.org/10.15252/embr.201643748"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28615291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28615291"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Riley Payne, Henry Hoff, Anne Roskowski, et al. 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