Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects

Cell Reports

Volumn 7, Issue 5, 2014, Pages 1679-1690

  Mullen, Andrew R ^a,f   Hu, Zeping ^a   Shi, Xiaolei ^a   Jiang, Lei ^a   Boroughs, Lindsey K ^a   Kovacs, Zoltan ^a   Boriack, Richard ^b   Rakheja, Dinesh ^b   Sullivan, Lucas B ^c,d   Linehan, W Marston ^e   Chandel, Navdeep S ^c,d   DeBerardinis, Ralph J ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c NORTHWESTERN UNIVERSITY   (United States)

^d NORTHWESTERN UNIVERSITY   (United States)

^e NATIONAL CANCER INSTITUTE   (United States)

^f WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 OXOGLUTARIC ACID; ISOCITRATE DEHYDROGENASE; NICOTINAMIDE ADENINE DINUCLEOTIDE (PHOSPHATE) TRANSHYDROGENASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SUCCINIC ACID; TRICARBOXYLIC ACID; ALPHA-KETOGLUTARIC ACID; FUMARATE HYDRATASE; NICOTINAMIDE ADENINE DINUCLEOTIDE;

AEROBIC METABOLISM; ARTICLE; CANCER CELL; CARBOXYLATION; CELL METABOLISM; CONTROLLED STUDY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ISOTOPE TRACING; METABOLOMICS; OXIDATION; OXIDATION REDUCTION STATE; PRIORITY JOURNAL; ANIMAL; CELL LINE; CITRIC ACID CYCLE; CRICETULUS; GENETICS; HAMSTER; HUMAN; METABOLISM; MITOCHONDRION; MUTATION; NEOPLASM; OXIDATION REDUCTION REACTION; TUMOR CELL LINE; DOWN REGULATION; GENE MUTATION; GENE SILENCING; MITOCHONDRIAL RESPIRATION; OSTEOSARCOMA CELL; PROTEIN DEPLETION; PROTEIN PROTEIN INTERACTION; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; UPREGULATION;

ANIMALS; CELL LINE; CELL LINE, TUMOR; CITRIC ACID CYCLE; CRICETINAE; CRICETULUS; FUMARATE HYDRATASE; HUMANS; ISOCITRATE DEHYDROGENASE; KETOGLUTARIC ACIDS; MITOCHONDRIA; MUTATION; NAD; NADP TRANSHYDROGENASE, AB-SPECIFIC; NEOPLASMS; OXIDATION-REDUCTION;

MAMMALIA;

EID: 84902343371     PISSN: None     EISSN: 22111247     Source Type: Journal    
DOI: 10.1016/j.celrep.2014.04.037     Document Type: Article

References (38)

1. Adam J., Yang M., Bauerschmidt C., Kitagawa M., O'Flaherty L., Maheswaran P., Özkan G., Sahgal N., Baban D., Kato K., et al. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 2013, 3:1440-1448.
2. Anastasiou D., Cantley L.C. Breathless cancer cells get fat on glutamine. Cell Res. 2012, 22:443-446.
3. Astuti D., Latif F., Dallol A., Dahia P.L., Douglas F., George E., Sköldberg F., Husebye E.S., Eng C., Maher E.R. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 2001, 69:49-54.
4. Baysal B.E., Ferrell R.E., Willett-Brozick J.E., Lawrence E.C., Myssiorek D., Bosch A., van der Mey A., Taschner P.E., Rubinstein W.S., Myers E.N., et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000, 287:848-851.
5. Cheng T., Sudderth J., Yang C., Mullen A.R., Jin E.S., Matés J.M., DeBerardinis R.J. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl. Acad. Sci. USA 2011, 108:8674-8679.
6. Dang L., White D.W., Gross S., Bennett B.D., Bittinger M.A., Driggers E.M., Fantin V.R., Jang H.G., Jin S., Keenan M.C., et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009, 462:739-744.
7. Deberardinis R.J., Sayed N., Ditsworth D., Thompson C.B. Brickby brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 2008, 18:54-61.
8. Fan T.W., Lane A.N., Higashi R.M., Farag M.A., Gao H., Bousamra M., Miller D.M. Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM). Mol. Cancer 2009, 8:41.
9. Fan J., Kamphorst J.J., Rabinowitz J.D., Shlomi T. Fatty acid labeling from glutamine in hypoxia can be explained by isotope exchange without net reductive IDH flux. J.Biol. Chem. 2013, 288:31363-31369.
10. Fendt S.M., Bell E.L., Keibler M.A., Olenchock B.A., Mayers J.R., Wasylenko T.M., Vokes N.I., Guarente L., Vander Heiden M.G., Stephanopoulos G. Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells. Nat. Commun. 2013, 4:2236.
11. Frezza C., Zheng L., Folger O., Rajagopalan K.N., MacKenzie E.D., Jerby L., Micaroni M., Chaneton B., Adam J., Hedley A., et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 2011, 477:225-228.
12. Gameiro P.A., Laviolette L.A., Kelleher J.K., Iliopoulos O., Stephanopoulos G. Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J.Biol. Chem. 2013, 288:12967-12977.
13. Gameiro P.A., Yang J., Metelo A.M., Pérez-Carro R., Baker R., Wang Z., Arreola A., Rathmell W.K., Olumi A., López-Larrubia P., et al. Invivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013, 17:372-385.
14. Hiller K., Metallo C.M. Profiling metabolic networks to study cancer metabolism. Curr. Opin. Biotechnol. 2013, 24:60-68.
15. Hochachka P.W., Storey K.B. Metabolic consequences of diving in animals and man. Science 1975, 187:613-621.
16. Hochachka P.W., Owen T.G., Allen J.F., Whittow G.C. Multiple end products of anaerobiosis in diving vertebrates. Comp. Biochem. Physiol. B 1975, 50:17-22.
17. Icard P., Poulain L., Lincet H. Understanding the central role of citrate in the metabolism of cancer cells. Biochim. Biophys. Acta 2012, 1825:111-116.
18. Kaelin W.G., McKnight S.L. Influence of metabolism on epigenetics and disease. Cell 2013, 153:56-69.
19. Killian J.K., Kim S.Y., Miettinen M., Smith C., Merino M., Tsokos M., Quezado M., Smith W.I., Jahromi M.S., Xekouki P., et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 2013, 3:648-657.
20. Leonardi R., Subramanian C., Jackowski S., Rock C.O. Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation. J.Biol. Chem. 2012, 287:14615-14620.
21. Marin-Valencia I., Yang C., Mashimo T., Cho S., Baek H., Yang X.L., Rajagopalan K.N., Maddie M., Vemireddy V., Zhao Z., et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain invivo. Cell Metab. 2012, 15:827-837.
22. Metallo C.M., Gameiro P.A., Bell E.L., Mattaini K.R., Yang J., Hiller K., Jewell C.M., Johnson Z.R., Irvine D.J., Guarente L., et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012, 481:380-384.
23. Mullen A.R., Wheaton W.W., Jin E.S., Chen P.H., Sullivan L.B., Cheng T., Yang Y., Linehan W.M., Chandel N.S., DeBerardinis R.J. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2012, 481:385-388.
24. Niemann S., Müller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 2000, 26:268-270.
25. O'Flaherty L., Adam J., Heather L.C., Zhdanov A.V., Chung Y.L., Miranda M.X., Croft J., Olpin S., Clarke K., Pugh C.W., et al. Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum. Mol. Genet. 2010, 19:3844-3851.
26. Rakheja D., Boriack R.L., Mitui M., Khokhar S., Holt S.A., Kapur P. Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate. Tumour Biol. 2011, 32:325-333.
27. Rakheja D., Mitui M., Boriack R.L., DeBerardinis R.J. Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors. Pediatr. Blood Cancer 2011, 56:379-383.
28. Rana M., de Coo I., Diaz F., Smeets H., Moraes C.T. An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann. Neurol. 2000, 48:774-781.
29. Reinecke C.J., Koekemoer G., van der Westhuizen F.H., Louw R., Lindeque J.Z., Mienie L.J., Smuts I. Metabolomics of urinary organic acids in respiratory chain deficiencies in children. Metabolomics 2012, 8:264-283.
30. Rzem R., Vincent M.F., Van Schaftingen E., Veiga-da-Cunha M. L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J.Inherit. Metab. Dis. 2007, 30:681-689.
31. Santidrian A.F., Matsuno-Yagi A., Ritland M., Seo B.B., LeBoeuf S.E., Gay L.J., Yagi T., Felding-Habermann B. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J.Clin. Invest. 2013, 123:1068-1081.
32. Sazanov L.A., Jackson J.B. Proton-translocating transhydrogenase and NAD- and NADP-linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria. FEBS Lett. 1994, 344:109-116.
33. Ternette N., Yang M., Laroyia M., Kitagawa M., O'Flaherty L., Wolhulter K., Igarashi K., Saito K., Kato K., Fischer R., et al. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency. Cell Rep. 2013, 3:689-700.
34. Tomitsuka E., Kita K., Esumi H. The NADH-fumarate reductase system, a novel mitochondrial energy metabolism, is a new target for anticancer therapy in tumor microenvironments. Ann. N Y Acad. Sci. 2010, 1201:44-49.
35. Tomlinson I.P., Alam N.A., Rowan A.J., Barclay E., Jaeger E.E., Kelsell D., Leigh I., Gorman P., Lamlum H., Rahman S., et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 2002, 30:406-410. Multiple Leiomyoma Consortium.
36. Weinberg J.M., Venkatachalam M.A., Roeser N.F., Nissim I. Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. Proc. Natl. Acad. Sci. USA 2000, 97:2826-2831.
37. Weinberg F., Hamanaka R., Wheaton W.W., Weinberg S., Joseph J., Lopez M., Kalyanaraman B., Mutlu G.M., Budinger G.R., Chandel N.S. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. USA 2010, 107:8788-8793.
38. Wise D.R., Ward P.S., Shay J.E., Cross J.R., Gruber J.J., Sachdeva U.M., Platt J.M., DeMatteo R.G., Simon M.C., Thompson C.B. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. USA 2011, 108:19611-19616.