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

Simple item page
dc.contributor.advisorBurgess, Shawn C.en
dc.contributor.committeeMemberAbrams, John M.en
dc.contributor.committeeMemberPearson, Gray W.en
dc.contributor.committeeMemberDeBerardinis, Ralph J.en
dc.creatorMullen, Andrew Robbinsen
dc.date.accessioned2016-01-05T19:34:21Z
dc.date.available2016-01-05T19:34:21Z
dc.date.created2013-12
dc.date.issued2013-10-23
dc.date.submittedDecember 2013
dc.date.updated2016-01-05T19:08:06Z
dc.description.abstractIn 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.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc933743766
dc.identifier.urihttps://hdl.handle.net/2152.5/2726
dc.language.isoenen
dc.subjectGlutamineen
dc.subjectMitochondriaen
dc.subjectNeoplasmsen
dc.titleReductive Carboxylation Is a Novel Pathway of Glutamine Metabolism That Supports the Growth of Tumor Cells with Metabolic Defectsen
dc.typeThesisen
dc.type.materialtexten
thesis.date.available2016-01-01
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineGenetics and Developmenten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
MULLEN-DISSERTATION-2013.pdf
Size:
4.24 MB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 4 of 4
No Thumbnail Available
Name:
LICENSE_3.txt
Size:
1.84 KB
Format:
Plain Text
Description:
Download
No Thumbnail Available
Name:
LICENSE_2.txt
Size:
1.84 KB
Format:
Plain Text
Description:
Download
No Thumbnail Available
Name:
LICENSE_1.txt
Size:
1.84 KB
Format:
Plain Text
Description:
Download
No Thumbnail Available
Name:
LICENSE.txt
Size:
1.84 KB
Format:
Plain Text
Description:
Download

Collections

UT Southwestern Graduate School of Biomedical Sciences