Lysosomal lipid logistics

forthcoming

Lysosomes are the central degradative organelle of all cells and function as logistic centres of cellular metabolite flux. Their dysregulation underlies ~70 monogenetic lysosomal storage disorders, metabolic syndromes, neurodegenerative maladies, and aging, thus affecting an ever-growing portion of the human population. A frequent denominator in these pathophysiological conditions is the deposition of lipids and lipid metabolites in the lysosomal lumen which leads to the accumulation of dysfunctional lysosomes, inflammatory responses, and cell death. The molecular mechanisms governing lipid flux through lysosomes are poorly understood, despite their importance for human disease. My proposed project will provide fundamental insights into the regulation of lysosomal lipid metabolism and thus pave the way for new therapeutic strategies. To achieve this, I will address two key aspects of lysosomal lipid logistics with direct implications in lysosomal lipid-dependent diseases: First, I will systematically interrogate the poorly understood mechanisms that establish and maintain the specialized lipid composition of the lysosomal limiting membrane. Second, I will uncover mechanisms that regulate the export of lipids and their metabolites from the lysosomal lumen into the cytoplasm. Finally, I aim to harness the findings to boost lysosomal membrane biogenesis and upregulate lipid metabolite export pathways to counteract pathologic lysosomal phenotypes in neurodegeneration-driving microglia cells. The results will provide unprecedented insight into the regulation of lysosomal lipid metabolism and will inform novel strategies to alleviate pathological phenotypes in human diseases with utmost societal importance.