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Modeling Regulation of Mitochondrial Free Ca2+ by Extra‐mitochondrial Mg2+ during ADP Phosphorylation

Mitochondrial free Ca2+ ([Ca2+]m) is regulated by Ca2+ influx via Ca2+ uniporter and Ca2+ efflux via Na+/Ca2+ exchanger as well as by Ca2+ buffering via mitochondrial metabolites and proteins. However, [Ca2+]m regulation during transient state‐3 respiration is not well understood. To test competing hypotheses and gain a quantitative understanding of [Ca2+]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 [Ca2+]m, [Ca2+]e, ΔΨm, [NADH]m, and matrix volume in guinea pig heart mitochondria suspended in Na+, Mg2+, and Ca2+ free buffer (1 mM EGTA) respiring with 0.5 mM pyruvic acid. Dynamics were inferred by adding CaCl2 (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 MgCl2, and ANT and F1F0‐ATPase blockers. Model analyses of the data suggest (a) [Ca2+]m is regulated by Ca2+ phosphate precipitation, (b) [Ca2+]m is a feedback inhibitor and [Mg2+]e is a competitive inhibitor of Ca2+ influx, (c) matrix [ADP] may activate Ca2+ influx during ADP phosphorylation, and (d) ATP synthesis leads to matrix contraction and contributes to the transient increases in [Ca2+]m during state‐3 respiration.