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Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease

Nature Cardiovascular Research volume 3, pages 500–514 (2024)Cite this article

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Abstract

The mitochondrial calcium (mCa2+) uniporter channel (mtCU) resides at the inner mitochondrial membrane and is required for Ca2+ to enter the mitochondrial matrix. The mtCU is essential for cellular function, as mCa2+ regulates metabolism, bioenergetics, signaling pathways and cell death. mCa2+ uptake is primarily regulated by the MICU family (MICU1, MICU2, MICU3), EF-hand-containing Ca2+-sensing proteins, which respond to cytosolic Ca2+ concentrations to modulate mtCU activity. Considering that mitochondrial function and Ca2+ signaling are ubiquitously disrupted in cardiovascular disease, mtCU function has been a hot area of investigation for the last decade. Here we provide an in-depth review of MICU-mediated regulation of mtCU structure and function, as well as potential mtCU-independent functions of these proteins. We detail their role in cardiac physiology and cardiovascular disease by highlighting the phenotypes of different mutant animal models, with an emphasis on therapeutic potential and targets of interest in this pathway.

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Fig. 1: mCa2+ influx and efflux machinery.
Fig. 2: mtCU-gatekeeping characteristics based on MICU association.
Fig. 3: MICU1 performs a variety of functions in the mitochondria.
Fig. 4: Tight regulation of mCa2+ is required to maintain basal physiological function.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) to J.W.E.: R01NS121379, P01HL147841 and an award from the American Heart Association to J.W.E.: 20EIA35320226.

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  1. Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

    Tyler L. Stevens, Henry M. Cohen, Joanne F. Garbincius & John W. Elrod

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  1. Tyler L. Stevens
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  2. Henry M. Cohen
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T.L.S., H.M.C., J.F.G. and J.W.E. all contributed toward the planning, writing and editing of this review.

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Correspondence to John W. Elrod.

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Stevens, T.L., Cohen, H.M., Garbincius, J.F. et al. Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease. Nat Cardiovasc Res 3, 500–514 (2024). https://doi.org/10.1038/s44161-024-00463-7

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