Conférence | A digital twin of oxidative metabolism to better understand the mechanisms underlying neurodegenerative diseases and ageing – Noelie Davezac, Restore

A digital twin of oxidative metabolism to better understand the mechanisms underlying neurodegenerative diseases and ageing.

Mitochondria play an essential role in the production of the energy required for cell function by generating adenosine triphosphate (ATP) through redox reactions, which are catalyzed by the five complexes of the mitochondrial respiratory chain. These reactions require electron transfer and, with oxygen, a superoxide anion is formed. Reactive oxygen species (ROS) are molecules derived from this superoxide anion. If not properly regulated by the antioxidant defenses, these ROS induce the oxidative stress. Complexes I and III of the mitochondrial respiratory chain have been identified as the main generators of ROS. When one or more of these respiratory complexes are altered, this can lead to oxidative stress at the cellular level. This mechanism is frequently associated with cancer, aging and many neurodegenerative diseases.
We modeled the catalytic mechanisms involved in the formation of ROS and their regulation by antioxidant defenses. We began by developing deterministic mathematical models representing the catalytic activity and ROS production of complex I and III individually. These models are based on rate equations, using the Michaelis and Menten formalism and biochemical data available in the literature. This approach makes it possible to build simple models capable of simulating the activity of complexes I and III, as well as their ROS production, under different conditions, and is easily modifiable and integrable into a more comprehensive model of the mitochondria.
Finally, the mathematical model of complex I was put to the test via a study on a model of neurodegenerative disease, dominant optic atrophy to provide a validation on the simulation of catalytic activity and a prediction on the ROS production of complex I and with fibroblasts from the INSPIRE T cohort concerning ageing.

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Noélie Davezac is a professor of molecular biology at the University of Toulouse. Following her PhD on the regulation of cell proliferation in 2002, she worked at the Necker Institute in Paris on the analysis of genetic diseases and the identification of therapeutic targets using omics-based approaches. In 2004, she was recruited to the University of Orsay (University of Saclay), where she continued her research. At the University of Toulouse 3, she worked on a genetic neurodegenerative disease, focusing on oxidative metabolism within the CBI, and in 2015, she introduced mathematical models to create digital twins of oxidative metabolism. She is the director of the Master’s programme in ‘Complex Systems in Life Sciences’, which focuses on modelling in biology and medicine. Finally, she is Deputy Vice-Chancellor for Research, responsible for science and society issues, at the University of Toulouse.