How do the nutrients we consume regulate our growth and homeostasis? Answering this question will help us understand not only how we develop, but also how we age and why we become susceptible to diseases as diverse as cancer, diabetes and neurodegeneration. After decades of research, we know surprisingly little on how nutrients are sensed within cells, and how nutrient-derived signals remodel the cell and enable it to adjust to changing metabolic requirements. Many intracellular compartments, bearing exotic names such as mitochondria, lysosomes and autophagosomes, specialize in storing, releasing and processing metabolites that range from amino acids to sugars, lipids and nucleotides. But how does each organelle sense the quality and quantity of the metabolites it carries? And how is this nutrient and energy information of each organelle communicated to other compartments in the cell?

© 2010 Macmillan Publishers Limited

© 2010 Macmillan Publishers Limited

To tackle these questions, we focus on the lysosome as our model system. Using advanced live cell microscopy, in vitro biochemical assays, and high throughput protein and metabolite profiling, we are discovering wonderful new properties of this organelle, which has traditionally been viewed as a metabolic end-point. Instead, the lysosome is emerging as a key signaling node, which relays nutrient availability to important signaling molecules such as the master growth regulatory kinase, mechanistic Target of Rapamycin Complex 1 (mTORC1).

© 2010 Macmillan Publishers Limited

© 2010 Macmillan Publishers Limited

The connection between the lysosome and mTORC1 has important implications for understanding the logic of metabolic regulation. mTORC1 drives biosynthetic processes such as ribosome biogenesis, mRNA translation and lipid synthesis. In turn, the lysosome mediates the breakdown of superfluous or damaged cellular components, thus providing a source of fuel and quality control for the cell. Our findings suggest that localized mTORC1 activation at the lysosome may provide a means for the cell to integrate biosynthetic and catabolic processes in space and time. Thus, elucidating the connection between mTORC1 and the lysosome may point the way to novel approaches for pathologies in which mass accumulation and cellular quality control are deranged, primarily in cancer and protein misfolding diseases.

© 2010 Macmillan Publishers Limited

© 2010 Macmillan Publishers Limited

We are investigating the lysosome as a metabolic ‘command and control’ center that i) functions as a signaling hub for nutrient sensing and signaling and ii) controls the storage and delivery of key substrates to the cell’s metabolic pathways. Exploring these exciting directions poses significant challenges. We do not yet have a comprehensive list of the lysosomal resident proteins and internal metabolites. Moreover, we do not understand how the lysosome’s many parts work together to regulate biophysical properties of this organelle such as its internal acidity and membrane potential. We will meet these challenges by developing novel techniques to probe organelle function both in vivo and in vitro, and by integrating them with advanced live cell microscopy and high throughput approaches.

funding