Abstract
Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
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Acknowledgements
The authors thank E. L. Seifert and D. Weaver for pre-reviewing the manuscript. This project was funded by NIH grants (RO1 DK125897, GM151536, NS132056 and RO3 TR004644).
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Glossary
- EF hand Ca2+-binding proteins
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A family of proteins that contain EF hand motifs, which is the structural unit that binds Ca2+.
- Electron probe X-ray microanalysis
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A technique that uses a focused beam of electrons to identify the chemical composition of solid materials.
- Fluorescence lifetime imaging microscopy
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(FLIM). An advanced imaging technique used to measure fluorescence decay rate (lifetime) instead of intensity.
- Genetically-encoded calcium indicators
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(GECI). Proteins used as reporters for cellular Ca2+ measurements, made possible by fusing Ca2+-binding motifs with fluorescent properties.
- PiC transporter
-
This phosphate carrier is an inner mitochondrial membrane protein involved in phosphate transport and mitochondrial ATP production, which has implications on mitochondrial Ca2+ transport and matrix Ca2+.
- Steatosis
-
The process in where the body accumulates lipids, affecting multiple organs and especially the liver in where this process is referred to as fatty liver disease.
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Cartes-Saavedra, B., Ghosh, A. & Hajnóczky, G. The roles of mitochondria in global and local intracellular calcium signalling. Nat Rev Mol Cell Biol 26, 456–475 (2025). https://doi.org/10.1038/s41580-024-00820-1
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DOI: https://doi.org/10.1038/s41580-024-00820-1
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