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.

Progress (September 2022)

Following an extensive review of the NNT literature, a first ODE-based (Ordinary Differential Equations) cellular model of integrated mitochondrial energy metabolism and redox homeostasis is currently being developed. The modelling efforts tightly link to experimental work focusing on the role of NNT in redox metabolism. This allows an iterative comparison between experimental data and the in silico model with respect to model structure, simulation and optimization.

In addition, this project synergizes 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.