Timothy WaiInstitut Pasteur / CNRS / Paris Descartes
Mes recherches
My research strategy builds upon frontier science in the areas of cell biology and biochemistry of mitochondria. In my lab we apply this knowledge to preclinical animal models and cellular models derived from patient biopsies to address fundamental translational knowledge gaps in rare genetic diseases of metabolism as well as common acquired age-associated diseases which include cardiovascular disease, cancer, and neurodegeneration. I obtained my PhD (2009) in Human Genetics at McGill University (Canada) under the supervision of Prof. Eric A. Shoubridge and then I carried out my post-doctoral fellowship in the laboratory of Prof. Thomas Langer at the Univeristy of Cologne/Max Planck Institute for the Biology of Ageing. I was recruited to the CNRS and obtained an ATIP-Avenir grant in 2015 to establish my independent research group “Mitochondrial dynamics and metabolism in health and disease” at the Institut Necker Enfants Malades in Paris beginning in 2016. Following my recruitment to the Institut Pasteur in 2017, I moved the laboratory in 2018 where I now head the G5 Mitochondrial Biology Group in the department of Cell Biology and Infection CNRS UMR 3691.
Mon projet ATIP-Avenir
Proteolytic regulation of mitochondrial dynamics and quality control in development and cardiovascular disease
Mitochondria are double membrane-bound organelles essential to virtually every cell of the body. Mutations in mitochondrial proteins cause inherited metabolic diseases but also contribute to more common disorders including neurodegeneration, cardiovascular disease, infertility, and ageing. Mitochondrial proteases are thought to maintain mitochondrial health by catalyzing the turnover of misfolded or mutant proteins and by governing regulatory processes such as mitochondrial dynamics. Mitochondrial membranes must fuse and divide to shape the form and function of the organelle in response to changes in metabolic demand. The balance of fusion and fission, maintained by OPA1 processing by the mitochondrial proteases YME1L and OMA1, is critical to life. Ablation of Yme1l disrupts this balance and causes embryonic lethality and cardiac-specific deletion of Yme1l causes chronic heart failure and middle-aged death, the latter of which can be rescued by high fat diet, suggesting a cardioprotective role of acquired glucose intolerance. The first aim of my research project is to (i) define the importance of YME1L and proteolytic regulation in the embryo. (ii) The second aim is to identify the circulating factors, signaling molecules, and breadth of protection high fat diet can provide in vivo. (iii) Lastly, we will explore how targeted disruption of mitochondrial protein quality control can be exploited to benefit disease states, by restoring the activity of the patient’s existing mutant gene product by preventing its otherwise rapid degradation. We believe that these proteomic and nutritional applications have the potential to be truly transformative and will pave the way for the development of new therapeutic interventions for both cardiovascular research and mitochondrial diseases alike.
Timothy Wai est également lauréat ERC Starting Grants 2016