Reductive Carboxylation Is a Novel Pathway of Glutamine Metabolism That Supports the Growth of Tumor Cells with Metabolic Defects

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In growing cancer cells, oxidative metabolism of glucose and glutamine in the mitochondria provide precursors needed for de novo synthesis of proteins, nucleic acids and lipids. Yet, a subset tumors harbor genetic mutations in the electron transport chain or tricarboxylic acid cycle that disable normal oxidative mitochondrial function. Importantly, it has been unknown how these cells generate the biosynthetic precursors required for growth. To address this, I used models of mitochondrial dysfunction in isogenic cancer cell lines and studied their metabolism using a combination of Gas Chromatography- Mass Spectrometry and Nuclear Magnetic Resonance spectroscopy. In all cases, mitochondrial dysfunction stimulated a novel pathway of glutamine metabolism, characterized by reversal of the canonical tricarboxylic acid cycle, termed reductive carboxylation; providing a plausible mechanism for how cancer cells with mitochondrial defects generate biosynthetic precursors required for growth. To gain mechanistic insight into how this unusual pathway was regulated I carried out a targeted metabolomics analysis in our isogenic tumor cell models. This led to the striking discovery that cells engaged in the reductive carboxylation pathway also operate an additional metabolic pathway that, at first glance, would appear to be superfluous and inefficient. Functional characterization of this second pathway revealed, however, that its activity was necessary for the optimal function of the reductive carboxylation pathway. In summary, this work has given us insights into how cancer cells are able to grow in the context of defective mitochondria. Additionally, this has exposed a potential Achilles ’ heel that might be used to selectively kill tumors which rely on this pathway for growth.

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