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Reductive carboxylation supports growth in tumour cells with defective mitochondria


Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells1,2. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis3. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function4,5,6,7, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP+/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.

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Figure 1: A reductive pathway of glutamine metabolism in cancer cells lacking activity of ETC complex III.
Figure 2: NADP + /NADPH-dependent isoforms of isocitrate dehydrogenase contribute to reductive carboxylation.
Figure 3: Glutamine is the major lipogenic precursor in cells lacking oxidative CAC function.
Figure 4: Glutamine-dependent reductive carboxylation in renal carcinoma cells lacking fumarate hydratase and during ETC inhibition in tumour cells with normal mitochondria.


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K. Uyeda and members of the DeBerardinis and Chandel laboratories provided critical assessment of the data, and J. Sudderth and C. Yang provided experimental assistance. We thank C. Moraes and I.F.M. de Coo for the WT 143B and CYTB 143B cell lines, I.E. Scheffler for CCL16-B2 cells and T. Yagi for CCL16-NDI1 cells. This work was supported by grants to R.J.D. from the NIH (K08DK072565 and R01CA157996), the Cancer Prevention and Research Institute of Texas (CPRIT, HIRP100437) and the Robert A. Welch Foundation (I1733); to N.S.C. from the NIH (R01CA123067), the LUNGevity Foundation and a Consortium of Independent Lung Health Organizations convened by Respiratory Health Association of Metropolitan Chicago; and to E.S.J. by an NIH grant (DK078933). The work was also supported by the Intramural Research Program of the NIH, National Cancer Institute Center for Cancer Research and by NIH grant RR02584. NIH training grants supported A.R.M. (5T32GM083831), W.W.W. (T32CA009560) and L.B.S. (T32GM008061). T.C. was supported by a CPRIT training grant.

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A.R.M., W.W.W., N.S.C. and R.J.D. designed the research. A.R.M., W.W.W., L.B.S., E.S.J., T.C. and P.-H.C. performed the experiments. A.R.M., W.W.W., L.B.S., E.S.J., P.-H.C., T.C., N.S.C. and R.J.D. analysed the data. Y.Y. and W.M.L. provided the FH-deficient (UOK262) cells. A.R.M., N.S.C. and R.J.D. wrote the paper.

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Correspondence to Navdeep S. Chandel or Ralph J. DeBerardinis.

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The authors declare no competing financial interests.

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Mullen, A., Wheaton, W., Jin, E. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012).

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