Networks of subcellular compartments in health and disease
Sinem Saka (EMBL) & Monther Abu-Remaileh (Stanford)
All cells fine tune their metabolic activity to maintain homeostasis by sensing and responding to intra- and extracellular perturbations. This necessitates a dynamic regulation of signaling and trafficking networks. Lysosomal function is one of the critical components for organismal homeostasis, and mutations in lysosomal genes cause severe diseases known as lysosomal storage diseases. Similarly, lysosomal dysfunction is emerging as a major hallmark in age-associated diseases including cancer, neurodegeneration and metabolic syndrome. Yet, it is unclear how lysosomal dysfunction affects other components of the cellular machinery and how the dynamic networks in cells compensate for the problems in one organelle.
In this project, we aim to answer two fundamental questions to establish how cells integrate internal and external factors to respond to perturbations or stress; 1) How do the morphology and dynamic network of organelles change in response to stress? and 2) How does this change in organellar morphology reflect cellular response? To achieve this, our labs will develop and apply new tools to understand how the communication between cellular compartments is altered under various metabolic states and disease conditions. We aim to create a catalog of these alterations in patient-derived cells and cell-based models of neurodegenerative diseases using next generation imaging approaches and omics tools by combining the expertise of the Abu-Remaileh Lab at Stanford and the Saka Group at EMBL Heidelberg.
1. Abu-Remaileh M., et al. “Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes.” Science (2017).
2. Gabriele, Markus D. Herrmann, and Lucas Pelkmans. "Multiplexed protein maps link subcellular organization to cellular states." Science 361.6401 (2018).
3. Sasaki, Kanae, and Hiderou Yoshida. "Organelle autoregulation—stress responses in the ER, Golgi, mitochondria and lysosome." The Journal of Biochemistry 157.4 (2015): 185-195. Gut,
4. Saka, Sinem K., et al. "Immuno-SABER enables highly multiplexed and amplified protein imaging in tissues." Nature biotechnology 37.9 (2019): 1080-1090.