Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.
The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5813975?pdf=render |
| _version_ | 1818922088484831232 |
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| author | Chisato Sumi Akihisa Okamoto Hiromasa Tanaka Kenichiro Nishi Munenori Kusunoki Tomohiro Shoji Takeo Uba Yoshiyuki Matsuo Takehiko Adachi Jun-Ichi Hayashi Keizo Takenaga Kiichi Hirota |
| author_facet | Chisato Sumi Akihisa Okamoto Hiromasa Tanaka Kenichiro Nishi Munenori Kusunoki Tomohiro Shoji Takeo Uba Yoshiyuki Matsuo Takehiko Adachi Jun-Ichi Hayashi Keizo Takenaga Kiichi Hirota |
| author_sort | Chisato Sumi |
| collection | DOAJ |
| description | The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propofol for prolonged periods. In vivo and in vitro evidence suggests that the propofol toxicity is related to the impaired mitochondrial function. However, underlying molecular mechanisms remain unknown. Therefore, we investigated effects of propofol on cell metabolism and death using a series of established cell lines of various origins, including neurons, myocytes, and trans-mitochondrial cybrids, with defined mitochondrial DNA deficits. We demonstrated that supraclinical concentrations of propofol in not less than 50 μM disturbed the mitochondrial function and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting mitochondrial complexes I, II and III. This disturbance in mitochondrial electron transport caused the generation of reactive oxygen species, resulting in apoptosis. We also found that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted propofol-induced caspase activation and cell death induced by clinical relevant concentrations of propofol in not more than 25 μM. With further experiments with appropriate in vivo model, it is possible that the processes to constitute the molecular basis of PRIS are identified. |
| first_indexed | 2024-12-20T01:47:59Z |
| format | Article |
| id | doaj.art-78013698f7764b45b6a4255777243335 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T01:47:59Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-78013698f7764b45b6a42557772433352022-12-21T19:57:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01132e019279610.1371/journal.pone.0192796Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.Chisato SumiAkihisa OkamotoHiromasa TanakaKenichiro NishiMunenori KusunokiTomohiro ShojiTakeo UbaYoshiyuki MatsuoTakehiko AdachiJun-Ichi HayashiKeizo TakenagaKiichi HirotaThe intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propofol for prolonged periods. In vivo and in vitro evidence suggests that the propofol toxicity is related to the impaired mitochondrial function. However, underlying molecular mechanisms remain unknown. Therefore, we investigated effects of propofol on cell metabolism and death using a series of established cell lines of various origins, including neurons, myocytes, and trans-mitochondrial cybrids, with defined mitochondrial DNA deficits. We demonstrated that supraclinical concentrations of propofol in not less than 50 μM disturbed the mitochondrial function and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting mitochondrial complexes I, II and III. This disturbance in mitochondrial electron transport caused the generation of reactive oxygen species, resulting in apoptosis. We also found that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted propofol-induced caspase activation and cell death induced by clinical relevant concentrations of propofol in not more than 25 μM. With further experiments with appropriate in vivo model, it is possible that the processes to constitute the molecular basis of PRIS are identified.http://europepmc.org/articles/PMC5813975?pdf=render |
| spellingShingle | Chisato Sumi Akihisa Okamoto Hiromasa Tanaka Kenichiro Nishi Munenori Kusunoki Tomohiro Shoji Takeo Uba Yoshiyuki Matsuo Takehiko Adachi Jun-Ichi Hayashi Keizo Takenaga Kiichi Hirota Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. PLoS ONE |
| title | Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. |
| title_full | Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. |
| title_fullStr | Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. |
| title_full_unstemmed | Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. |
| title_short | Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. |
| title_sort | propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain dependent manner |
| url | http://europepmc.org/articles/PMC5813975?pdf=render |
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