Mechanistic basis of EMRE's essential role in the regulation of mitochondrial calcium uniporter complex

Authors

Kumari, A., Nguyen, D. M., Disilvestre, D., Dirda, N. D. A., Kethanapalli, S. H., Kao, J. P. Y., Garg, V.

Abstract

Mitochondrial Ca2+ uptake through the mitochondrial calcium uniporter complex (MCUcx) is a critical determinant of cellular metabolism, integrating Ca2+ signaling with ATP production and redox control. Yet how MCUcx activity is constrained to prevent Ca2+ overload and cell injury, and how the essential MCU regulator (EMRE), a subunit required for channel activity, mechanistically supports MCUcx function remains incompletely defined. Here, using a newly developed high-sensitivity assay to quantify MCUcx function in intact mitochondria, we uncover two fundamental roles of EMRE. First, EMRE is required for robust matrix Ca2+-dependent inhibition of MCUcx, acting through a juxtamembrane site via a mechanism distinct from MICU1-mediated inhibition at low cytosolic Ca2+. Second, by decoupling channel function from regulation, we demonstrate that EMRE promotes robust ion permeation through MCUcx, elevating its role from a structural scaffold to an active determinant of channel throughput. Together, our findings refine current models of mitochondrial Ca2+ regulation, establish EMRE as an essential multifunctional regulator of uniporter activity, and highlight the utility of our assay for probing MCUcx biophysical mechanisms and enabling the discovery of uniporter modulators.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Jun 2026.

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