Unveiling the molecular mechanisms to modulate peroxisome dynamics and abundance for improvement of cell performance

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One of the hallmarks of eukaryotic cells is the presence of membrane-bound compartments (organelles), which create different optimised environments to promote various metabolic reactions required to sustain life. To adapt to the changing physiological requirements of a cell or organism, organelles have to constantly adjust their number, shape, position, and metabolic functions accordingly. This requires dynamic processes which modulate organelle abundance by organelle formation (biogenesis), degradation (autophagy), or inheritance (cell division). Peroxisomes are multifunctional subcellular organelles that are essential for human health and development. Vital, protective roles of peroxisomes in lipid metabolism, signalling, the combat of oxidative stress and ageing have emerged recently. Our work has revealed that peroxisomes are extremely dynamic and can form from pre-existing organelles in a multistep process which requires remodelling of the peroxisomal membrane, the formation of tubular membrane extensions which subsequently constrict and divide into several new peroxisomes. Defects in peroxisome dynamics and multiplication have been linked to age related disorders involving neurodegeneration, loss of sight and deafness. Despite their fundamental importance to cell physiology, the mechanisms that mediate and regulate peroxisome membrane dynamics and abundance in humans are poorly understood and a biophysical model is missing. Understanding these mechanisms is not only important for comprehending fundamental physiological processes but also for understanding pathogenic processes in disease etiology. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions.In this research project, we will (1) assess the role of key proteins in peroxisome division to unveil the molecular mechanisms modulating peroxisome abundance, (2) apply biophysical approaches to investigate protein-lipid interaction and membrane remodelling, (3) identify mechanisms to modulate expression of key proteins and peroxisome dynamics for improvement of cell performance, and (4) develop a biophysical/mathematical model to understand and predict peroxisome dynamics in health and disease conditions.In summary, in this interdisciplinary project we will combine unique complementary expertise in organelle-biology and organelle-based disorders with biophysical and mathematical approaches as well as novel tools and models in human cell biology. We will apply molecular cell biology, biophysical, biochemical and screening approaches, mathematical modelling and cutting edge imaging techniques to reveal the molecular mechanisms and pathways that mediate and regulate organelle membrane dynamics and organelle abundance. Specifically, this research project will improve our understanding of organelle dynamics/abundance and its impact on healthy ageing and common, degenerative disorders. We will generate new tools and models for assessing and modulating organelle dynamics, which may help to improve cell performance. Understanding how to modulate organelle dynamics and abundance and to use the protective functions of organelles will be of significant biological and medical importance. It may contribute to the development of new therapeutic approaches in healthy ageing and age-related disorders.