Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells
Reductively metabolized glutamine is a major cellular carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here we identify several cellular conditions where the α-ket...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/91505 https://orcid.org/0000-0002-8956-5117 https://orcid.org/0000-0002-8607-1787 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-5410-6543 https://orcid.org/0000-0003-4064-2510 https://orcid.org/0000-0001-6909-4568 |
| _version_ | 1811082009712263168 |
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| author | Fendt, Sarah-Maria Bell, Eric L. Mayers, Jared R. Vokes, Natalie I. Stephanopoulos, Gregory Keibler, Mark Andrew Wasylenko, Thomas Michael Guarente, Leonard Pershing Vander Heiden, Matthew G. Olenchock, Benjamin |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Fendt, Sarah-Maria Bell, Eric L. Mayers, Jared R. Vokes, Natalie I. Stephanopoulos, Gregory Keibler, Mark Andrew Wasylenko, Thomas Michael Guarente, Leonard Pershing Vander Heiden, Matthew G. Olenchock, Benjamin |
| author_sort | Fendt, Sarah-Maria |
| collection | MIT |
| description | Reductively metabolized glutamine is a major cellular carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here we identify several cellular conditions where the α-ketoglutarate/citrate ratio is changed due to an altered acetyl-CoA to citrate conversion, and demonstrate that reductive glutamine metabolism is initiated in response to perturbations that result in an increase in the α-ketoglutarate/citrate ratio. Thus, targeting reductive glutamine conversion for a therapeutic benefit might require distinct modulations of metabolite concentrations rather than targeting the upstream signalling, which only indirectly affects the process. |
| first_indexed | 2024-09-23T11:55:56Z |
| format | Article |
| id | mit-1721.1/91505 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:55:56Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/915052022-10-01T07:01:58Z Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells Fendt, Sarah-Maria Bell, Eric L. Mayers, Jared R. Vokes, Natalie I. Stephanopoulos, Gregory Keibler, Mark Andrew Wasylenko, Thomas Michael Guarente, Leonard Pershing Vander Heiden, Matthew G. Olenchock, Benjamin Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Fendt, Sarah-Maria Keibler, Mark Andrew Wasylenko, Thomas Michael Stephanopoulos, Gregory Bell, Eric L. Mayers, Jared R. Guarente, Leonard Pershing Vander Heiden, Matthew G. Olenchock, Benjamin Vokes, Natalie I. Reductively metabolized glutamine is a major cellular carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here we identify several cellular conditions where the α-ketoglutarate/citrate ratio is changed due to an altered acetyl-CoA to citrate conversion, and demonstrate that reductive glutamine metabolism is initiated in response to perturbations that result in an increase in the α-ketoglutarate/citrate ratio. Thus, targeting reductive glutamine conversion for a therapeutic benefit might require distinct modulations of metabolite concentrations rather than targeting the upstream signalling, which only indirectly affects the process. German Science Foundation (Grant FE1185) National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship F32 CA132358) National Institutes of Health (U.S.) (Grant 5-P30-CA14051-39) Damon Runyon Cancer Research Foundation Burroughs Wellcome Fund Smith Family Foundation National Institutes of Health (U.S.) (Grant 1R01CA160458-01A1) 2014-11-07T19:00:02Z 2014-11-07T19:00:02Z 2013-07 2012-12 Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/91505 Fendt, Sarah-Maria, Eric L. Bell, Mark A. Keibler, Benjamin A. Olenchock, Jared R. Mayers, Thomas M. Wasylenko, Natalie I. Vokes, Leonard Guarente, Matthew G. Vander Heiden, and Gregory Stephanopoulos. “Reductive Glutamine Metabolism Is a Function of the α-Ketoglutarate to Citrate Ratio in Cells.” Nature Communications 4 (July 31, 2013). https://orcid.org/0000-0002-8956-5117 https://orcid.org/0000-0002-8607-1787 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-5410-6543 https://orcid.org/0000-0003-4064-2510 https://orcid.org/0000-0001-6909-4568 en_US http://dx.doi.org/10.1038/ncomms3236 Nature Communications Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Fendt, Sarah-Maria Bell, Eric L. Mayers, Jared R. Vokes, Natalie I. Stephanopoulos, Gregory Keibler, Mark Andrew Wasylenko, Thomas Michael Guarente, Leonard Pershing Vander Heiden, Matthew G. Olenchock, Benjamin Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells |
| title | Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells |
| title_full | Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells |
| title_fullStr | Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells |
| title_full_unstemmed | Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells |
| title_short | Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells |
| title_sort | reductive glutamine metabolism is a function of the α ketoglutarate to citrate ratio in cells |
| url | http://hdl.handle.net/1721.1/91505 https://orcid.org/0000-0002-8956-5117 https://orcid.org/0000-0002-8607-1787 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-5410-6543 https://orcid.org/0000-0003-4064-2510 https://orcid.org/0000-0001-6909-4568 |
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