Document Type

Article

Publication Date

12-23-2025

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This article is the author's final published version in Cell Reports, Volume 44, Issue 12, December 2025, Article Number 116583.

The published version is available at https://doi.org/10.1016/j.celrep.2025.116583. Copyright © 2025 The Author(s). 

Abstract

Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise in primary cortical neurons, leading to neuronal overmigration in the cortex and behavioral changes at 2 but not 12 months. Consistently, mitochondrial calcium uptake is not significantly affected in the adult animal cortex. MICU2-deficient patient fibroblasts copy the mitochondria-confined calcium alteration in developing neurons. Thus, MICU2 is important during neurodevelopment, likely by regulating the mtCU, and is eliminated by brain maturation.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Additional Files
FiguresS1-S7 & Table S1.pdf (3186 kB)

PubMed ID

41273721

Language

English

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