Mitochondrial Ca2+ dynamics in cells and suspensions

• Published in: The FEBS journal 2017-12, Vol.284 (23), p.4128-4142
• Main Authors: Wacquier, Benjamin, Romero Campos, Hugo E., González‐Vélez, Virginia, Combettes, Laurent, Dupont, Geneviève
• Format: Article
• Language: English
• Subjects: Calcium (mitochondrial); calcium dynamics; Calcium signalling; cardiac cells; computational modelling; Computer applications; Endoplasmic reticulum; Exchanging; Fluxes; hepatocytes; Kinetics; Membranes; Mitochondria; mitochondrial calcium uniporter; Na+/Ca2+ exchanger; Reaction kinetics
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14296

Mitochondria play a significant role in shaping cytosolic Ca2+ signals. Thus, transfer of Ca2+ across the mitochondrial membrane is much studied, not only in intact cells but also in artificial systems such as mitochondrial suspensions or permeabilised cells. Observed rates of Ca2+ changes vary by at least one order of magnitude. In this work, we investigate the relationship between the Ca2+ dynamics observed in various experimental conditions using a computational model calibrated on experimental data. Results confirm that mitochondrial Ca2+ exchange fluxes through the mitochondrial Ca2+ uniporter (MCU) and the Na+/Ca2+ exchanger obey the same basic kinetics in cells and in suspensions, and emphasise the important role played by the high Ca2+ levels reached in mitochondria‐associated endoplasmic reticulum membranes in intact cells. Tissue specificity can be ascribed to the different modes of regulation of the MCU by Ca2+, probably related to the specific levels of expression of the Ca2+ sensing regulator subunit of this channel. The model emphasises the importance of mitochondrial density and buffering in controlling the rate of Ca2+ exchanges with mitochondria, as verified experimentally. Finally, we show that heterogeneity between individual mitochondria can explain the large range of amplitudes and rates of rise in mitochondrial Ca2+ concentration that have been observed experimentally. Fluxes of Ca2+ across the mitochondrial membranes are important for signalling and bioenergetics. Ca2+ exchanges between mitochondria and the extra‐mitochondrial medium can be studied not only in intact cells, but also in suspensions or in permeabilised cells, leading to very different profiles of Ca2+ changes. However, they all obey the same kinetics whatever the experimental conditions and the cell type.