The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis

Abstract

Dysregulation of the pathways that preserve mitochondrial integrity hallmarks many human diseases including diabetes, neurodegeration, aging and cancer. The mitochondrial citrate transporter gene, SLC25A1 or CIC, maps on chromosome 22q11.21, a region amplified in some tumors and deleted in developmental disorders known as velo-cardio-facial- and DiGeorge syndromes. We report here that in tumor cells CIC maintains mitochondrial integrity and bioenergetics, protects from mitochondrial damage and circumvents mitochondrial depletion via autophagy, hence promoting proliferation. CIC levels are increased in human cancers and its inhibition has anti-tumor activity, albeit with no toxicity on adult normal tissues. The knock-down of the CIC gene in zebrafish leads to mitochondria depletion and to proliferation defects that recapitulate features of human velo-cardio-facial syndrome, a phenotype rescued by blocking autophagy. Our findings reveal that CIC maintains mitochondrial homeostasis in metabolically active, high proliferating tissues and imply that this protein is a therapeutic target in cancer and likely, in other human diseases.

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

“…Interestingly, the knockdown of SLC25A1 in zebrafish leads to mitochondria depletion and to proliferation defects that recapitulate features of the human velo-cardio-facial syndrome (i.e. cardiac defects, facial and jaw anomalies, and cleft palate) phenotype rescued by blocking autophagy (58). Although the concentration of 2HG was significantly higher in 22qDS plasma compared with controls, it was below that observed in patients with combined DL-2-hydroxyglutaric aciduria (3-50-fold of control levels; calculated from Ref.…”

Citrate – new functions for an old metabolite

“…Two approaches have been used to identify these new functions. The first is based on the inhibition of mitochondrial CIC activity by the specific substrate analogue 1,2,3-benzene-tricarboxylate (BTA) Infantino et al, 2011a;Cappello et al, 2012;Catalina-Rodriguez et al, 2012) and the second by siRNA gene silencing Morciano et al, 2009;Infantino et al, 2011a;Catalina-Rodriguez et al, 2012). Recently, by mutational analysis of the SLC25A1 gene (Edvardson et al, 2013;Nota et al, 2013), different mutations were identified in patients with agenesis of corpus callosum and hydroxyglutaric aciduria.…”

“…RTK, receptor tyrosine kinase; GLUT1, glucose transporter 1; GLS, glutaminase. Unauthenticated Download Date | 5/12/18 11:03 AM Recently, Catalina-Rodriguez et al (2012) demonstrated that CIC is much more expressed in cancer cells, suggesting an increased need for citrate in cancer cells. This metabolic requirement protects the cancer cells' mitochondria through the inhibition of glycolysis, promotion of mitochondrial OXPHOS and ATP production, and stabilization of the mitochondrial membrane potential.…”

“…This metabolic requirement protects the cancer cells' mitochondria through the inhibition of glycolysis, promotion of mitochondrial OXPHOS and ATP production, and stabilization of the mitochondrial membrane potential. On the contrary, when the CIC gene is silenced by siRNA or the CIC activity is inhibited by BTA, its adaptive protection activity is abolished, the respiratory capacity is compromised, the ROS level increases, and the mitochondria are subjected to autophagy (Catalina-Rodriguez et al, 2012). As a consequence of CIC inhibition, the tumor cells die.…”

“…This results in altered histone methylation marks and dysregulated cellular differentiation. Taking into consideration that the CIC gene has previously been implicated in epigenetic and cancer biology (Morciano et al, 2009;Wellen et al, 2009;Catalina-Rodriguez et al, 2012) and that CIC gene defect causes elevation of 2-HG (see section Citrate in Neurodevelopmental Syndromes and Hydroxyglutaric Aciduria), the previous hypothesis needs to be further focused and investigated. It is interesting to note that 2-HG can also increase in the absence of metabolic enzyme mutations.…”