Dissecting the role of mitochondrial glutathione homeostasis in cancer

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Project Summary All eukaryotic cells, whether normal or cancerous, require the ability to sense changes in nutrients levels, ensuring their efficient use for survival and growth. Nutrient sensing mechanisms enable cells to rapidly adapt to environmental perturbation, a feature particularly essential for cancer cells to overcome diverse metabolic stresses along the metastatic cascade. Although many nutrient sensing mechanisms have been described, how metabolites are sensed in subcellular compartments remains a major open question. This question is particularly relevant for redox-active molecules such as NAD and glutathione, which display remarkably heterogenous distribution across subcellular compartments and have been shown to play key roles in cancer metastasis. Recent breakthroughs in deorphanizing mitochondrial metabolite transporters provided unprecedented opportunity to probe the dynamics and sensing mechanism of these metabolites at subcellular precision. In a recently published study, SLC25A39 has been identified as a key transporter for mitochondrial glutathione, a major antioxidant molecule implicated in cancer progression and metastasis. Remarkably, evidence suggests that SLC25A39 undergoes feedback regulation by mitochondrial glutathione and may be required for efficient metastatic colonization, implicating it in an adaptive mechanism for cancers to overcome metabolic stress during metastasis. This proposal seeks a deeper understanding of the implication of organellar glutathione metabolism in cancer. The Aim 1 of this proposal seeks to understand the role of mitochondrial glutathione homeostasis in tumor progression and metastasis and decipher the mechanism of its regulation. The Aim 2 of this proposal seeks to develop novel genetically encoded, single-cell RNAseq-compatible reporters for profiling intercellular heterogeneity in mitochondrial glutathione in tumors. Using a combination of biochemical analysis, unbiased CRISPR screens and novel animal models, this proposal aims to paint a multilayered picture of the dynamics, regulatory mechanisms and functional contribution of mitochondrial glutathione homeostasis in tumor progression and metastasis. Completion of the proposed studies will deepen our understanding on the role of compartmentalized metabolite pools in metabolic rewiring of cancers and shed light on novel therapeutic strategies to target metastasis.