Modeling Dynamic Regulation of Mitochondrial free Ca2+: Effects of Ca2+ Sequestration and Precipitation

Abstract

One of the most intriguing features of cardiac mitochondria is their ability to accumulate, retain and release enormous amount of Ca2+ via sophisticated Ca2+ transport and buffering systems. Mitochondrial free Ca2+ ([Ca2+]m) is mainly regulated by integrated function of Ca2+ uptake and extrusion pathways and Ca2+ sequestration and precipitation mechanisms. In spite of significant studies on the kinetics and regulation of mitochondrial Ca2+ transport systems, the mechanisms involved in mitochondrial Ca2+ sequestration and precipitation remain obscure. Here we developed a detailed computational model by integrating our recent biophysical models of cation transporters and a novel Ca2+ sequestration mechanism into our existing model of mitochondrial bioenergetics to quantitatively understand the dynamic regulation of [Ca2+]m. Experiments were conducted to measure time course of [Ca2+]m, [Ca2+]e, [NADH]m and pH in guinea pig heart mitochondria suspended in buffer media subjected to incremental concentrations of CaCl2 (0–40 μM) and NaCl (0–20 mM). Model analyses of the data suggest (1) with a constant Ca2+ buffering capacity, it is not possible to explain the dynamics of [Ca2+]m, (2) [Ca2+]m is largely influenced by a Ca2+‐dependent Ca2+ sequestration mechanism and least affected by Ca2+‐phosphate precipitation and, (3) there may be additional pathways for Ca2+ uptake (RaM), apart from the Ca2+ uniporter.