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Identification of sources and functions of metabolic capacitance in the ATP metabolic network in muscle
Author(s) -
van Stiphout Ruud P.G.M.,
Verhoog Peter J,
van Riel Natal A.W.,
Jeneson Jeroen A.L.
Publication year - 2006
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.20.4.a410-c
Subject(s) - calcium , oxidative phosphorylation , biophysics , mitochondrion , adenosine triphosphate , chemistry , biochemistry , biology , organic chemistry
Muscle contraction is activated by oscillatory calcium signals. Since calcium is known to boost oxidative ATP supply, mitochondrial ATP output could well become oscillatory during muscle activity. If so, this could interfere with calcium homeostasis given the high sensitivity to ATP free energy potential concomitant with full kinetic reversibility of calcium pumps. Here, we used computational modeling to identify and test sources of metabolic capacitance in the ATP metabolic network in muscle with respect to low‐pass filtering of mitochondrial ATP output. We built a lumped, kinetic model of calcium‐activated oxidative ATP metabolism in muscle with a calcium‐sensing mitochondrion (Ngyen & Jafri 2005) at its core. Cytosolic components included basal‐ and calcium‐activated ATPases, adenylate and creatine pools and kinases, and an oscillatory calcium input signal. Computations were performed in MATLAB and solved by imposing mass balance constraint. Physiological endpoints such as matrix‐ and cytosolic redox and ATP free energy potentials were computed for validation. We observed the classic creatine kinase capacitance function buffering amplitude and rate of ATP potential drop during activation of metabolism by the calcium input signal. This function was lost after in silico knock out. However, the network failed to filter the oscillation of the input signal, resulting in a 2 kJ/mole oscillation of cytosolic ATP free energy potential. These results suggest that metabolic capacitance is needed inside the mitochondrion to protect calcium homeostasis in muscle.