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Effect of Extra‐Matrix Mg 2+ on Matrix Free Ca 2+ : Analysis by an Integrated Model of Mitochondrial Ca 2+ Handling
Author(s) -
Pradhan Ranjan K,
Boelens Age D,
Bazil Jason,
Camara Amadou K.S.,
Stowe David F,
Beard Daniel A,
Dash Ranjan K
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.732.8
Mitochondrial free Ca 2+ ([Ca 2+ ] m ) is regulated by the integrated function of various Ca 2+ transport pathways and Ca 2+ buffering by metabolites and proteins. Mg 2+ is known to influence many energy‐dependent transport and metabolic processes, including regulation of [Ca 2+ ] m by inhibiting Ca 2+ uniporter and interacting with Ca 2+ buffering metabolites and proteins. To gain a quantitative understanding of the interacting effects of Mg 2+ and Ca 2+ on the dynamic regulation of [Ca 2+ ] m and bioenergetics, we developed here a detailed computational model by integrating our recent biophysical models of cation transporters into our existing model of mitochondrial bioenergetics. The model accounts for binding and buffering of cations with metabolites and proteins, including ATP, ADP and Pi. Experiments were conducted to measure the dynamics of [Ca 2+ ] m , [Ca 2+ ] e , [NADH] m and Δψ m with addition of 0, 0.25, 0.4, 0.5, 0.6 and 0.75 mM CaCl 2 followed by 250 μM ADP in respiring mitochondria of guinea pig hearts suspended in buffer containing 1 mM EGTA and 0, 0.125, 0.25, 0.5, 1, 2 and 5 mM MgCl 2 . Model analyses of the [Ca 2+ ] m and [Ca 2+ ] e data suggests (1) [Ca 2+ ] m is largely regulated by Ca 2+ ‐phosphate precipitation at ≈1μM [Ca 2+ ] m , and (2) there may be two distinct pathways for Ca 2+ uptake, one is a rapid‐mode uptake which is independent of Mg 2+ and the other is a Ca 2+ uniporter which is dose‐dependently inhibited by Mg 2+ .