A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels
Altered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714002629 |
| _version_ | 1819154276396564480 |
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| author | Nathan J. Lanning Brendan D. Looyenga Audra L. Kauffman Natalie M. Niemi Jessica Sudderth Ralph J. DeBerardinis Jeffrey P. MacKeigan |
| author_facet | Nathan J. Lanning Brendan D. Looyenga Audra L. Kauffman Natalie M. Niemi Jessica Sudderth Ralph J. DeBerardinis Jeffrey P. MacKeigan |
| author_sort | Nathan J. Lanning |
| collection | DOAJ |
| description | Altered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions in order to examine their effects on cellular ATP levels. We identified a mechanism by which electron transport chain (ETC) perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux, thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels and AMPK signaling and whose expression significantly correlates with glioma patient survival. This study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome. |
| first_indexed | 2024-12-22T15:18:30Z |
| format | Article |
| id | doaj.art-da142fcd883240b8a28c4b9f3921e3b7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T15:18:30Z |
| publishDate | 2014-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-da142fcd883240b8a28c4b9f3921e3b72022-12-21T18:21:41ZengElsevierCell Reports2211-12472014-05-017390791710.1016/j.celrep.2014.03.065A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP LevelsNathan J. Lanning0Brendan D. Looyenga1Audra L. Kauffman2Natalie M. Niemi3Jessica Sudderth4Ralph J. DeBerardinis5Jeffrey P. MacKeigan6Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USALaboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USALaboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USALaboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USADepartment of Pediatrics, Children’s Medical Center Research Institute, and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USADepartment of Pediatrics, Children’s Medical Center Research Institute, and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USALaboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USAAltered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions in order to examine their effects on cellular ATP levels. We identified a mechanism by which electron transport chain (ETC) perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux, thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels and AMPK signaling and whose expression significantly correlates with glioma patient survival. This study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.http://www.sciencedirect.com/science/article/pii/S2211124714002629 |
| spellingShingle | Nathan J. Lanning Brendan D. Looyenga Audra L. Kauffman Natalie M. Niemi Jessica Sudderth Ralph J. DeBerardinis Jeffrey P. MacKeigan A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels Cell Reports |
| title | A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels |
| title_full | A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels |
| title_fullStr | A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels |
| title_full_unstemmed | A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels |
| title_short | A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels |
| title_sort | mitochondrial rnai screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of atp levels |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714002629 |
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