Key result
Substitution of the physiological Mg2+ cofactor with Ca2+ disrupts the positive cooperativity of F1FO-ATPase ATP hydrolysis, shifting the Hill coefficient from 2.01 to 1.41.
Why the study?
Does substitution of Mg2+ with Ca2+ alter the kinetics of F1FO-ATPase ATP hydrolysis?
Does substitution of Mg2+ with Ca2+ alter the kinetics of F1FO-ATPase ATP hydrolysis?
Absolute Event Rate: 1.41% vs 2.01%
Substitution of the physiological Mg2+ cofactor with Ca2+ shifts F1FO-ATPase ATP hydrolysis kinetics from positive cooperativity to Michaelian, acting as an uncompetitive inhibitor.
May influence cardiac mitochondrial bioenergetics under Ca2+ overload; leaves open clinical relevance for heart failure or ischemia.
The mitochondrial F 1 F O -ATPase is a dual-function enzyme that synthesizes ATP using the proton motive force and hydrolyzes ATP to reenergize the membrane. Mg 2+ is the physiological cofactor of F 1 F O -ATPase, enabling both ATP synthesis and hydrolysis, while Ca 2+ supports only ATP hydrolysis. Mg 2+ -dependent F 1 F O -ATPase exhibits positive cooperativity in ATP hydrolysis Hill coefficient (nHi) of 2.01 ± 0.21, whereas Ca 2+ -dependent activity shows Michaelian kinetics, nHi 1.41 ± 0.06. Ca 2+ acts as an uncompetitive inhibitor on Mg 2+ -dependent ATP hydrolysis, suggesting distinct binding sites and conformational effects. The differential kinetic behavior underlies the enzyme's multifunctionality of F 1 F O -ATPase in physio-pathological conditions, depending on the cofactor. • Mg 2+ enables cooperative ATP hydrolysis; Ca 2+ shifts kinetics toward Michaelian. • Ca 2+ supports ATP hydrolysis only and inhibits uncompetitively Mg 2+ -dependent F 1 F O -ATPase. • Distinct Mg 2+ /Ca 2+ effects tune F 1 F O -ATPase function(s) in health and disease.
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Algieri et al. (2026) studied this question. Ca2+ substitution vs. Mg2+ was evaluated on Hill coefficient (nHi) for ATP hydrolysis. Substitution of the physiological Mg2+ cofactor with Ca2+ disrupts the positive cooperativity of F1FO-ATPase ATP hydrolysis, shifting the Hill coefficient from 2.01 to 1.41.
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