Role of the Mitochondrial Citrate Transporter, SLC25A1, in Cancer, Obesity and Liver Steatosis
Mosaoa, Rami Muath
Avantaggiati, Maria Laura
Alterations in metabolism lead to disruption of normal tissue homeostasis and are hallmarks of many human diseases, including cancer, diabetes and obesity. This work focuses on the mitochondrial transporter Slc25a1, which promotes the flux of the essential metabolic substrate, citrate, across the mitochondrial membrane. We have shown that Slc25a1 is necessary for multiple branches of metabolism, contributing to the utilization of carbohydrates, lipids, and to the regulation of oxidative phosphorylation (OXPHOS), a primary mechanism by which cells derive energy. The first study investigates how Slc25a1 influences the immune response against tumors, an area of great interest in the cancer field. Upregulation of Programmed Death-Ligand-1 (PD-L1) or of its receptor, Programmed Cell Death Protein 1 (PD-1), allows tumor cells to escape immune surveillance and, accordingly, monoclonal antibodies inhibiting PD-L1/PD-1 (immune checkpoint inhibitors, ICIs), promote the elimination of tumors by the immune system. ICIs have shown extraordinary success in the clinic, but only in a subset of patients, driving intense research towards the identification of the molecular determinants of response or resistance. We have found that tumors with high levels of Slc25a1 display a significantly better response to ICIs, while low levels of Slc25a1 correlate with resistance. Mechanistically, we attribute this favorable response to the ability of Slc25a1 to enhance the levels of PD-L1, making it available for antibody targeting, and to generate a pro-inflammatory environment that facilitates tumor killing. These findings imply for the first time that Slc25a1 is an important contributor to the anti-tumor immune response and may provide a useful biomarker predictive of ICI outcomes. The second study builds upon the concept that citrate is necessary for lipid metabolism and investigates the role of this protein in obesity, diabetes and obesity-driven non-alcoholic fatty liver disease (NAFLD), all conditions that also increase cancer risk and for which there are very limited therapeutic options. We demonstrate that in mouse models of diet-induced NAFLD, inhibition of Slc25a1 with a specific compound, CTPI-2, completely prevents lipid build up in the liver (steatosis), also starkly mitigating obesity. Importantly, mice treated with CTPI-2 could afford a very high fat dietetic regimen for a prolonged period of time, but without developing significant liver damage, obesity or disruption of glucose homeostasis. Mechanistically, in addition to regulation of lipid synthesis, we show for the first time that Slc25a1 inhibition also blunts gluconeogenesis, which is primarily involved in the regulation of the blood glucose levels, leading to normalization of hyperglycemia and glucose tolerance. Our data reveal for the first time that Slc25a1 provides a potentially exploitable novel therapeutic target for preventing diet-induced obesity and liver pathology.
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