Reductive carboxylation supports growth in tumor cells with defective mitochondria

By A. Mullen, W. Wheaton, Eunsook S. Jin, Pei-Hsuan Chen, Lucas B. Sullivan, Tzuling Cheng, Youfeng Yang, W. Marston Linehan, Navdeep S. Chandel, Ralph J. Deberardinis and 2 more. Nature, 2011

1,311 citations recorded by the source corpus.

Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. 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 tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/93a03f41cfe5ed8ecdd2786d31f14d6b0a5ceecc

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Citations in the corpus

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis (2014, neutral): “Furthermore, cancer cells have been shown to conduct glutamine-dependent reductive carboxylation to generate the TCA cycle intermediates required for cell proliferation when the electron transport chain is inhibited (Mullen et al., 2012; Fendt et al., 2013).”
Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “In these circumstances, glutamine directly supplies carbons for citrate production and fatty acid synthesis (78, 81, 82).”
Posttranscriptional control of T cell effector function by aerobic glycolysis. (2013, neutral): “See also Figures S1 and S2. metabolism due to mutations in the ETC or TCA cycle, hypoxia, or culture with mitochondrial inhibitors use reductive carboxylation of a-ketoglutarate to produce citrate and other precursors during growth and proliferation (Metallo et al., 2012; Mullen et al., 2012).”
Mitochondrial metabolism and cancer (2017, background): “Reductive glutamine metabolism is the major source of citrate in the presence of mitochondrial defects, as well as under hypoxic conditions (as a function of the α-KG/citrate ratio) [23, 73, 87].”
Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). (2012, background): “…recently showed that tumor cells with mutations in complex I or III of the electron transport chain (ETC) used glutamine-dependent reductive carboxylation as the major pathway of citrate formation, suggesting that glutamine supports tumor growth in various pathways in defective mitochondria (49).”
Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development (2013, background): “However, recent evidence suggests that cancer cells are also able to generate citrate for FA biosynthesis through the reductive metabolism of glutamine (Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “In place of oxidative metabolism of both glucose and glutamine, these cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon (Le et al., 2012; Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
Links between metabolism and cancer. (2012, background): “In fact, glutamine could contribute to citrate and lipid metabolism through the reversal of the TCA cycle or reductive carboxylation of aKG by isocitrate dehydrogenase (IDH) to form citrate or through forward cycling of glutamine carbons (Fig. 2; Wise et al. 2011; Metallo et al. 2012; Mullen et al. ”
Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells (2015, background): “In 143BCytB cells, which metabolize glutamine by reductive carboxylation (Figure 5B and S4B) (Mullen et al., 2012), glutamate levels are only”
Mitochondria and Cancer (2016, background): “Alternatively, and less commonly, a-ketoglutarate can undergo reductive carboxylation to generate isocitrate and citrate and, eventually, 2C units for fat synthesis (Mullen et al., 2012).”
Fundamentals of cancer metabolism (2016, background): “Furthermore, if pyruvate oxidation to acetyl-CoA is compromised by hypoxia or ETC impairment, glutamine can provide acetylCoA as a biosynthetic precursor to sustain tumor growth (69, 78, 79).”