Computational analysis of Ca 2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca 2+ uptake
Year: 2014
Type: article
Abstract: Key points Cytosolic, but not matrix, Mg 2+ inhibits mitochondrial Ca 2+ uptake through the Ca 2+ uniporter (CU). The majority of mitochondrial Ca 2+ uptake under physiological levels of cytosolic Ca 2+ and Mg 2+ is through a fast uptake pathway, namely the ryanodine receptor (RyR)‐type channel (RTC), that has characteristics similar to the ryanodine receptor. Modulation of mitochondrial RTC adaptation and opening probability by cytosolic Mg 2+ is not robust, in contrast to that of cardiac sarcoplasmic reticulum RyR. Model analysis of the mitochondrial Ca 2+ sequestration system further validates the existence of two different classes of Ca 2+ buffering proteins, i.e. Class 1 and Class 2. The Ca 2+ buffering capacity of Class 1 protein is auto‐regulated by the rate at which Ca 2+ is taken up by cardiac mitochondria. The quantitative framework suggests differential roles for the two modes of Ca 2+ uptake pathways: CU–Ca 2+ buffering, and RTC–Ca 2+ modulated bioenergetics. Abstract Cardiac mitochondria can act as a significant Ca 2+ sink and shape cytosolic Ca 2+ signals affecting various cellular processes, such as energy metabolism and excitation–contraction coupling. However, different mitochondrial Ca 2+ uptake mechanisms are still not well understood. In this study, we analysed recently published Ca 2+ uptake experiments performed on isolated guinea pig cardiac mitochondria using a computer model of mitochondrial bioenergetics and cation handling. The model analyses of the data suggest that the majority of mitochondrial Ca 2+ uptake, at physiological levels of cytosolic Ca 2+ and Mg 2+ , occurs through a fast Ca 2+ uptake pathway, which is neither the Ca 2+ uniporter nor the rapid mode of Ca 2+ uptake. This fast Ca 2+ uptake component was explained by including a biophysical model of the ryanodine receptor (RyR) in the computer model. However, the Mg 2+ ‐dependent enhancement of the RyR adaptation was not evident in this RyR‐type channel, in contrast to that of cardiac sarcoplasmic reticulum RyR. The extended computer model is corroborated by simulating an independent experimental dataset, featuring mitochondrial Ca 2+ uptake, egress and sequestration. The model analyses of the two datasets validate the existence of two classes of Ca 2+ buffers that comprise the mitochondrial Ca 2+ sequestration system. The modelling study further indicates that the Ca 2+ buffers respond differentially depending on the source of Ca 2+ uptake. In particular, it suggests that the Class 1 Ca 2+ buffering capacity is auto‐regulated by the rate at which Ca 2+ is taken up by mitochondria.
Source: The Journal of Physiology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1479927002