INTER-ORGANELLE COMMUNICATION IN METABOLIC CONTROL

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In order to execute its pro-anabolic and pro-catabolic programs, the lysosome engages in extensive interactions, both physically and functionally, with other membrane-bound organelles. For example during autophagy, a ‘self-eat’ process that clears superfluous or damaged cellular components, lysosomes fuse with double-membraned autophagosomes, allowing the cargo molecules captured by the autophagosome to be delivered to the lysosomal lumen for degradation. However, the factors that regulate autophagosome-lysosome interaction remain poorly understood.

In addition to direct fusion, the lysosome engages in stable physical junctions known as membrane contact sites (MCSs) with other membrane compartments. The MCSs provide the lysosome with a direct route for the exchange lipids, ions and other metabolically relevant signals. However, the full range of inter-organelle interactions, and how they impact lysosome-dependent metabolic programs (i.e. mTORC1 signaling) are wide-open questions. Combining live cell microscopy, high-throughput genetic screens and mass spectrometry-based profiling of specific organelle populations, we are conducting in-depth investigations of how the lysosome interfaces with other important organelles such as ER, autophagosomes, mitochondria and lipid droplets (link). Our ultimate goal is to discover organelle-based metabolic circuits and dissect their physiological roles in different cellular and physiological contexts. An especially exciting avenue is understanding how cancer cells rewire the composition and function of their organellar circuitries in order to achieve growth and adaptive advantages.