Bibliographic Details
| Title: |
An enzyme kinetic model for quantitative interpretation of the role of nicotinamide nucleotide transhydrogenase (NNT) in cell physiology. |
| Authors: |
Gan, Zhuohui1 (AUTHOR) ganzoe@protonmail.com, van der Stelt, Inge1 (AUTHOR) inge.vanderstelt@wur.nl, Grefte, Sander1 (AUTHOR) sander.grefte@wur.nl, Suarez Diez, Maria2 (AUTHOR) maria.suarezdiez@wur.nl, Koopman, Werner J.H.1,3 (AUTHOR) werner.koopman@radboudumc.nl, Keijer, Jaap1 (AUTHOR) jaap.keijer@wur.nl |
| Source: |
Free Radical Biology & Medicine. Oct2026, Vol. 254, p660-675. 16p. |
| Subject Terms: |
*Enzyme kinetics, *Nicotinamide adenine dinucleotide phosphate, *Mitochondrial membranes, *Mathematical models, *Mitochondria, *Homeostasis, *NAD(P)H dehydrogenases |
| Abstract: |
Nicotinamide Nucleotide Transhydrogenase (NNT) connects mitochondrial bioenergetics and redox homeostasis. It catalyzes a reversible reaction that couples proton transport across the mitochondrial inner membrane (MIM) to hydride transfer between mitochondrial NAD(H) and NADP(H). Understanding NNT kinetics is essential to decipher the link between NNT and mitochondrial functioning. Based on the protein structure and the molecular mechanism of NNT, we deduced that the kinetic mechanism of NNT can be described by a "ping-pong" mechanism. Integrated with its thermodynamic features, we established a mathematical model to describe its enzyme kinetics. The model successfully simulated experimental results obtained in submitochondrial particles. Further model analyses suggest that NNT operates in the forward mode under most physiological conditions, whereas reverse-mode action occurs under specific conditions, including mitochondrial membrane potential depolarization. Additionally, our analyses suggest that during physiological conditions, the NNT-mediated reaction is more sensitive to changes in redox homeostasis than changes in mitochondrial bioenergetics, as evidenced by a larger effect of the redox ratio of NADP(H) than that of NAD(H). [Display omitted] • Nicotinamide nucleotide transhydrogenase = mitochondrial inner membrane enzyme NNT. • NNT catalyzes NADH + NADP+ ↔ NAD+ + NADPH using the proton motive force (Δp). • We developed an NNT enzyme kinetic model and validated it against experimental data. • Redox state, especially of NADP(H), but not Δp, governs the forward NNT reaction. • In physiological range forward reaction, reverse reaction to prevent Δp collapse. [ABSTRACT FROM AUTHOR] |
| Database: |
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