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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.

SUBMITTER: Catalina-Rodriguez O

PROVIDER: S-EPMC3717962 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Catalina-Rodriguez Olga O Kolukula Vamsi K VK Tomita York Y Preet Anju A Palmieri Ferdinando F Wellstein Anton A Byers Stephen S Giaccia Amato J AJ Glasgow Eric E Albanese Chris C Avantaggiati Maria Laura ML

Oncotarget 20121001 10

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 c ...[more]

PMID: 23100451

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Project description:Pronounced resistance of lung cancer cells to radiotherapy and chemotherapy is a major barrier to successful treatment. Herein, both tumor hypoxia and the upregulation of the cellular antioxidant defense systems observed during malignant progression can contribute to radioresistance. We recently found that exposure to chronic cycling severe hypoxia/reoxygenation stress results in glutamine-dependent upregulation of cellular glutathione (GSH) levels and associated radiation resistance opening novel routes for tumor cell-specific radiosensitization. Here, we explored the role of the mitochondrial citrate carrier (SLC25A1) for the improved antioxidant defense of cancer cells with tolerance to acute and chronic severe hypoxia/reoxygenation stress and the use of pharmacologic SLC25A1 inhibition for tumor cell radiosensitization. Exposure to acute or chronic cycling severe hypoxia/reoxygenation stress triggered upregulated expression of SLC25A1 in lung cancer, prostate cancer, and glioblastoma cells in vitro. Interestingly, exposure to ionizing radiation (IR) further promoted SLC25A1 expression. Inhibition of SLC25A1 by 1,2,3-benzene-tricarboxylic acid (BTA) disturbed cellular and mitochondrial redox homeostasis, lowered mitochondrial metabolism, and reduced metabolic flexibility of cancer cells. Even more important, combining IR with BTA was able to overcome increased radioresistance induced by adaptation to chronic cycling severe hypoxia/reoxygenation stress. This radiosensitizing effect of BTA-treated cells was linked to increased reactive oxygen species and reduced DNA repair capacity. Of note, key findings could be reproduced when using the SLC25A1-inhibitor 4-Chloro-3-[[(3-nitrophenyl)amino]sulfonyl]-benzoic acid (CNASB). Moreover, in silico analysis of publically available databases applying the Kaplan-Meier plotter tool (kmplot.com) revealed that overexpression of SLC25A1 was associated with reduced survival of lung cancer patients suggesting a potential link to aggressive cancers. We show that SLC25A1 can contribute to the increased antioxidant defense of cancer cells allowing them to escape the cytotoxic effects of IR. Since upregulation of SLC25A1 is induced by adverse conditions in the tumor environment, exposure to IR, or both pharmacologic inhibition of SLC25A1 might be an effective strategy for radiosensitization of cancer cells particularly in chronically hypoxic tumor fractions.

Project description:BACKGROUND:Mitochondrial dysfunction has been implicated in the pathologies of a number of retinal degenerative diseases in both the outer and inner retina. In the outer retina, photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and sensitivity to oxidative stress. However, it is unclear how defective mitochondrial biogenesis affects neural development and contributes to neural degeneration. In this report, we investigated the in vivo function of nuclear respiratory factor 1 (Nrf1), a major transcriptional regulator of mitochondrial biogenesis in both proliferating retinal progenitor cells (RPCs) and postmitotic rod photoreceptor cells (PRs). METHODS:We used mouse genetic techniques to generate RPC-specific and rod PR-specific Nrf1 conditional knockout mouse models. We then applied a comprehensive set of tools, including histopathological and molecular analyses, RNA-seq, and electroretinography on these mouse lines to study Nrf1-regulated genes and Nrf1's roles in both developing retinas and differentiated rod PRs. For all comparisons between genotypes, a two-tailed two-sample student's t-test was used. Results were considered significant when P <?0.05. RESULTS:We uncovered essential roles of Nrf1 in cell proliferation in RPCs, cell migration and survival of newly specified retinal ganglion cells (RGCs), neurite outgrowth in retinal explants, reconfiguration of metabolic pathways in RPCs, and mitochondrial morphology, position, and function in rod PRs. CONCLUSIONS:Our findings provide in vivo evidence that Nrf1 and Nrf1-mediated pathways have context-dependent and cell-state-specific functions during neural development, and disruption of Nrf1-mediated mitochondrial biogenesis in rod PRs results in impaired mitochondria and a slow, progressive degeneration of rod PRs. These results offer new insights into the roles of Nrf1 in retinal development and neuronal homeostasis and the differential sensitivities of diverse neuronal tissues and cell types of dysfunctional mitochondria. Moreover, the conditional Nrf1 allele we have generated provides the opportunity to develop novel mouse models to understand how defective mitochondrial biogenesis contributes to the pathologies and disease progression of several neurodegenerative diseases, including glaucoma, age-related macular degeneration, Parkinson's diseases, and Huntington's disease.

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

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

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