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

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 mutationsin SLC25A13, manifesting clinically in growth failure that can be alleviated by dietary restriction of carbohydrates. The association of citrinwith glycolysisand NAD+/NADH ratio led us to hypothesize that it may play a role in carcinogenesis. Indeed, we find that citrinis upregulated in multiple cancer types and is essential for supplementing NAD+ for glycolysisand NADH for oxidative phosphorylation. Consequently, citrindeficiency associates with autophagy, whereas its overexpression in cancer cells increases energy production and cancer invasion. Furthermore, based on the human deleterious mutationsin citrin, we found a potential inhibitor of citrinthat restricts cancerous phenotypes in cells. Collectively, our findings suggest that targeting citrinmay be of benefit for cancer therapy.