Project

The functional role of nicotinamide nucleotide transhydrogenase (NNT)

The integration between mitochondrial bioenergetics and redox homeostasis plays a central role in mammalian physiology. To enhance the understanding of these complex interacting systems, the researchers of this project aim to develop mathematic models that quantitatively describe the key pathways involved. Important substrates include ATP, ADP, NAD(H) and NADP(H). Nicotinamide Nucleotide Transhydrogenase (NNT), which transfers a hydride between NADH and NADPH, fulfils a key role in the coupling between mitochondria-mediated energy production and redox metabolism.

However, it is still unclear how NNT action mechanistically impacts mitochondrial and cellular physiology in health and disease. Therefore, NNT+/+ and NNT-/- mice and cell models with identical genetic backgrounds are used. In this sense, the mathematical models will not only help to understand the biochemical function of specific model components (e.g. NNT) but might also provide information relevant for interventions in metabolic disease.

This project synergises with: (1) an NLAS complex cell system project on muscle-nerve interaction using pluripotent stem cells and primary NNT+/+ and NNT-/- cells, (2) research on the interaction between ex vivo muscles and nerves and (3) a project focusing on the development of cell models expressing proteinaceous fluorescent biosensors.

Progress (September 2023)

Using the recently published structure and the proposed catalytic mechanism of the mitochondrial inner membrane protein nicotinamide nucleotide transferase (NNT), an ODE-based enzymatic kinetic model has been developed to interpret the NNT mediated reaction. The developed model predicted experimental data. The researchers aim to publish this before March 2024. To better understand the role of NNT in the cellular environment, a prototype model with the presentation of NNT to interpret cell bioenergy has been developed, but various kinetic parameters needed for full implementation are lacking. Therefore, this model is now being condensed to facilitate experimental verification using data that can be reasonably generated in the lab. The generated model will allow better understanding of the functional role of this disease-relevant protein.