Bio

Bio


The Abu-Remaileh Lab is interested in identifying novel pathways that enable cellular and organismal adaptation to metabolic stress and changes in environmental conditions. We also study how these pathways go awry in human diseases such as cancer, neurodegeneration and metabolic syndrome, in order to engineer new therapeutic modalities.

To address these questions, our lab uses a multidisciplinary approach to study the biochemical functions of the lysosome in vitro and in vivo. Lysosomes are membrane-bound compartments that degrade macromolecules and clear damaged organelles to enable cellular adaptation to various metabolic states. Lysosomal function is critical for organismal homeostasis—mutations in genes encoding lysosomal proteins cause severe human disorders known as lysosomal storage diseases, and lysosome dysfunction is implicated in age-associated diseases including cancer, neurodegeneration and metabolic syndrome.

By developing novel tools and harnessing the power of metabolomics, proteomics and functional genomics, our lab will define 1) how the lysosome communicates with other cellular compartments to fulfill the metabolic demands of the cell under various metabolic states, 2) and how its dysfunction leads to rare and common human diseases. Using insights from our research, we will engineer novel therapies to modulate the pathways that govern human disease.

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  • Maintaining Iron Homeostasis Is the Key Role of Lysosomal Acidity for Cell Proliferation. Molecular cell Weber, R. A., Yen, F. S., Nicholson, S. P., Alwaseem, H., Bayraktar, E. C., Alam, M., Timson, R. C., La, K., Abu-Remaileh, M., Molina, H., Birsoy, K. 2020

    Abstract

    The lysosome is an acidic multi-functional organelle with roles in macromolecular digestion, nutrient sensing, and signaling. However, why cells require acidic lysosomes to proliferate and which nutrients become limiting under lysosomal dysfunction are unclear. To address this, we performed CRISPR-Cas9-based genetic screens and identified cholesterol biosynthesis and iron uptake as essential metabolic pathways when lysosomal pH is altered. While cholesterol synthesis is only necessary, iron is both necessary and sufficient for cell proliferation under lysosomal dysfunction. Remarkably, iron supplementation restores cell proliferation under both pharmacologic and genetic-mediated lysosomal dysfunction. The rescue was independent of metabolic or signaling changes classically associated with increased lysosomal pH, uncoupling lysosomal function from cell proliferation. Finally, our experiments revealed that lysosomal dysfunction dramatically alters mitochondrial metabolism and hypoxia inducible factor (HIF) signaling due to iron depletion. Altogether, these findings identify iron homeostasis as the key function of lysosomal acidity for cell proliferation.

    View details for DOI 10.1016/j.molcel.2020.01.003

    View details for PubMedID 31983508