The mitochondrial carrier Citrin plays a role in regulating cellular energy during carcinogenesis

• Published in: Oncogene Vol. 39; no. 1; pp. 164 - 175
• Main Authors: Rabinovich, Shiran, Silberman, Alon, Adler, Lital, Agron, Shani, Levin-Zaidman, Smadar, Bahat, Amir, Porat, Ziv, Ben-Zeev, Efrat, Geva, Inbal, Itkin, Maxim, Malitsky, Sergey, Buchaklian, Adam, Helbling, Daniel, Dimmock, David, Erez, Ayelet
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.01.2020; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: 101/58; 13/106; 13/109; 13/31; 13/89; 14; 14/28; 14/35; 38; 631/67/1813/1634; 631/67/2327; 82; Apoptosis; Aspartate; Autophagy; Cancer; Carbohydrates; Carbohydrates - genetics; Carcinogenesis; Carcinogenesis - genetics; Cell Biology; Citrullinemia - genetics; Citrullinemia - metabolism; Cytosol; Cytosol - metabolism; Cytosol - pathology; Dietary restrictions; Gene Expression Regulation, Neoplastic - genetics; Gene mutations; Genetic aspects; Germ-Line Mutation - genetics; Glucose metabolism; Glutamates - pharmacology; Glutamic Acid - analogs & derivatives; Glutamic Acid - pharmacology; Glycolysis; Glycolysis - genetics; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Membrane Transport Proteins - genetics; Molecular Targeted Therapy; Mutation; NAD; NADH; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Oncology; Optics; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Phagocytosis; Phenotypes; Phosphorylation; Physics; Israel; Cancer metabolism; Melanoma
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0976-2

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.