Citrin, encoded by SLC25A13 gene, is an inner mitochondrial transporter that is part of the malate–aspartate shuttle, which regulates the NAD+/NADH ratio between the cytosol and mitochondria. Citrullinemia type II (CTLN-II) is an inherited disorder caused by germline mutations in SLC25A13, manifesting clinically in growth failure that can be alleviated by dietary restriction of carbohydrates. The association of citrin with glycolysis and NAD+/NADH ratio led us to hypothesize that it may play a role in carcinogenesis. Indeed, we find that citrin is upregulated in multiple cancer types and is essential for supplementing NAD+ for glycolysis and NADH for oxidative phosphorylation. Consequently, citrin deficiency associates with autophagy, whereas its overexpression in cancer cells increases energy production and cancer invasion. Furthermore, based on the human deleterious mutations in citrin, we found a potential inhibitor of citrin that restricts cancerous phenotypes in cells. Collectively, our findings suggest that targeting citrin may be of benefit for cancer therapy.
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We acknowledge and thank the Weizmann Institute for providing financial and infrastructural support. We thank Tomer Shlomi and his student Won Dong-Lee, Gad Asher, Zvulun Elazar and his student Adi Abada, Yoav Shaul, Irit Sagi, Ron Rotkopf, and Sivan Galai for the intellectual and technical assistance. AE is incumbent of the Leah Omenn Career Development Chair and is supported by research grants from the European research program (CIG618113, ERC614204), the Israel Science Foundation (1343/13; 1952/13), and from the Minerva grant award (711730). AE received additional support from the Adelis Foundation, the Henry S. and Anne S. Reich Research Fund, the Dukler Fund for Cancer Research, the Paul Sparr Foundation, the Saul and Theresa Esman Foundation, from Joseph Piko Baruch, and from the estate of Fannie Sherr. The authors declare applying for a patent for citrin inhibition as cancer therapy.
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Rabinovich, S., Silberman, A., Adler, L. et al. The mitochondrial carrier Citrin plays a role in regulating cellular energy during carcinogenesis. Oncogene 39, 164–175 (2020). https://doi.org/10.1038/s41388-019-0976-2
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