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Modeling Regulation of Mitochondrial Free Ca 2+ by Extra‐mitochondrial Mg 2+ during ADP Phosphorylation
Author(s) -
Dash Ranjan K,
Pradhan Ranjan K,
Agarwal Bhawana,
Boelens Age D,
Haumann Johan,
Camara Amadou KS,
Stowe David F
Publication year - 2010
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.24.1_supplement.1048.4
Subject(s) - uniporter , chemistry , mitochondrion , mitochondrial matrix , biophysics , bioenergetics , egta , atp–adp translocase , calcium , biochemistry , inner mitochondrial membrane , cytosol , biology , enzyme , organic chemistry
Mitochondrial free Ca 2+ ([Ca 2+ ] m ) is regulated by Ca 2+ influx via Ca 2+ uniporter and Ca 2+ efflux via Na + /Ca 2+ exchanger as well as by Ca 2+ buffering via mitochondrial metabolites and proteins. However, [Ca 2+ ] m regulation during transient state‐3 respiration is not well understood. To test competing hypotheses and gain a quantitative understanding of [Ca 2+ ] m regulation, we developed a detailed computational model by integrating our recent biophysical models of cation transporters into our existing model of mitochondrial bioenergetics. The model also accounts for binding and buffering of cations with proteins and metabolites, including ATP, ADP and Pi. Experiments were conducted to measure [Ca 2+ ] m , [Ca 2+ ] e , ΔΨ m , [NADH] m , and matrix volume in guinea pig heart mitochondria suspended in Na + , Mg 2+ , and Ca 2+ free buffer (1 mM EGTA) respiring with 0.5 mM pyruvic acid. Dynamics were inferred by adding CaCl 2 (0.25, 0.5, 0.65, 0.75, 0.85, 1.0 mM) followed by 250 μM ADP with or without 25 μM RuR, 1 mM MgCl 2 , and ANT and F 1 F 0 ‐ATPase blockers. Model analyses of the data suggest (a) [Ca 2+ ] m is regulated by Ca 2+ phosphate precipitation, (b) [Ca 2+ ] m is a feedback inhibitor and [Mg 2+ ] e is a competitive inhibitor of Ca 2+ influx, (c) matrix [ADP] may activate Ca 2+ influx during ADP phosphorylation, and (d) ATP synthesis leads to matrix contraction and contributes to the transient increases in [Ca 2+ ] m during state‐3 respiration.