Lysosome dysfunction in the pathogenesis of kidney diseases

Lysosomes are the main degradative compartment of eukaryotic cells; they represent the endpoint of different endocytic pathways and of the self-catabolic process known as autophagy. Their capacity to degrade a vast array of macromolecules, thanks to an arsenal of different hydrolases, enables them to remove toxic cellular material as well as damaged organelles, shut off signal transduction pathways, and recycle macromolecules’ building blocks, in particular amino acids. The lysosomal ability to scavenge nutrients from proteolytic degradation is particularly relevant for cancer cells, which have increased energy demands and generally must grow and proliferate in nutrient-poor microenvironments. In addition to its degradative function, the lysosome also has a crucial role in the regulation of signalling pathways that control cellular anabolism. In particular, the lysosome is the cellular hub for the nutrient-sensing signalling pathway orchestrated by the kinase complex mTORC1, master regulator of cell growth and metabolism. Mutations of different key players of this nutrient-sensing lysosomal machinery have been implicated in cancer while frequently mutated oncogenic pathways, such as the PI3K/AKT or the MAPK pathway, also result in mTORC1 hyperactivation. In addition, we recently discovered that excessive activation of MiT/TFE factors, master regulators of lysosome biogenesis and function, also promotes mTORC1 hyperactivation, which fuels the growth of different malignancies, in particular kidney cancer. In our lab, we are interested in dissecting how lysosomal dysfunction and, in particular, mTORC1 signalling deregulation may contribute to the pathogenesis of different genetic disorders characterized by kidney cystogenesis and cancer. Although kidney cysts and tumours represent distinct pathological conditions, common pathways could underline both diseases and we hypothesize that lysosomal dysfunction is highly implicated in these renal manifestations; hence targeting the lysosome may represent a potent therapeutic strategy. In the lab we combine mouse genetics and cell biological tools, specifically biochemistry, immuno-fluorescence imaging, proteomics and transcriptomics in cellular and murine models, aiming to identify novel molecular targets for the treatment of kidney cystogenesis and cancer. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.