Mitochondrial Ca²⁺ dynamics in cells and suspensions

Abstract

Mitochondria play a significant role in shaping cytosolic Ca signals. Thus, transfer of Ca 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 Ca changes vary by at least one order of magnitude. In this work, we investigate the relationship between the Ca dynamics observed in various experimental conditions using a computational model calibrated on experimental data. Results confirm that mitochondrial Ca exchange fluxes through the mitochondrial Ca uniporter (MCU) and the Na /Ca exchanger obey the same basic kinetics in cells and in suspensions, and emphasise the important role played by the high Ca 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 Ca , probably related to the specific levels of expression of the Ca sensing regulator subunit of this channel. The model emphasises the importance of mitochondrial density and buffering in controlling the rate of Ca 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 Ca concentration that have been observed experimentally.

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

“…These regulators allow a fine tuning of the opening of the MCU pore (Mammucari et al 2018;Nemani et al 2018;Penna et al 2018) and modulate the sigmoidal dependence on Ca 2+ of the MCU (Csordás et al 2013;Patron et al 2014). Specific stoichiometries between the MCU and its regulators may be responsible for the observed tissue-specific differences of activities of the uniporter, and explains, for example, the variation in Ca 2+ dynamics observed in mitochondria of heart and liver (Paillard et al 2017;Wacquier et al 2017). Indeed, as MICU1 is less expressed in cardiomyocytes, the Ca 2+ uptake rate is higher at low cytosolic Ca 2+ concentrations, but smaller at high cytosolic Ca 2+ levels, as compared with hepatocytes that express much more MICU1.…”

“…This tissue-specific MICU1:MCU expression ratio is highly relevant as heart cells characterized by a liver-like MICU1:MCU expression ratio display contractile dysfunction (Paillard et al 2017). Interestingly, in modeling approaches, it is possible to provide a unifying description of mitochondrial Ca 2+ dynamics in different cell types by taking into account the level of expression of the MCU (which is lower in heart cells [Fieni et al 2012]) and the MICU1:MCU expression ratio (Wacquier et al 2017). As a matter of fact, the regulation of the MCU is highly sophisticated and is covered in detail in recent reviews Nemani et al 2018;Wang et al 2018).…”

A mathematical model of mitochondrial calcium-phosphate dissolution as a mechanism for persistent post-CSD vasoconstriction

“…Our chief modification to prior models has been the explicit handling of calcium buffering. Many prior studies assumed that a fixed proportion of calcium is buffered [6,5,66]. This assumption is an approximate form of the rapid buffer approximation that we use in this study.…”

“…where the cytosolic volume is assumed to be 0.7 pL and the mitochondrial volume ratio is taken from Wacquier et al [66]. We assume that calcium is well-mixed within each compartment, denoting the compartmental concentrations as…”

“…In formulating our model, we inherited some assumptions of prior work [66,30,48,39,21,40]. We relied on prior models for understanding the dynamical implications of elevated mitochondrial calcium and on measurements on mesenteric smooth rather than cerebral smooth muscle cells.…”