Mitochondrial Ca2+ dynamics in cells and suspensions

Abstract

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.

Keywords: calcium dynamics; cardiac cells; computational modelling; hepatocytes; mitochondrial calcium uniporter.