title: 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.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Catalina-Rodriguez
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Kolukula
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Anju
authors.initials: A
authors.lastname: Preet
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: Stephen
authors.initials: S
authors.lastname: Byers
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.forename: Eric
authors.initials: E
authors.lastname: Glasgow
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D006706:Homeostasis; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics
chemical_list: C498610:CIC protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D000255:Adenosine Triphosphate