Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.
Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity,...
| 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/PMC6093661?pdf=render |
| _version_ | 1818518234788265984 |
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| author | Andrew Hinman Charles R Holst Joey C Latham Joel J Bruegger Gözde Ulas Kevin P McCusker Akiko Amagata Dana Davis Kevin G Hoff Amanda H Kahn-Kirby Virna Kim Yuko Kosaka Edgar Lee Stephanie A Malone Janet J Mei Steve James Richards Veronica Rivera Guy Miller Jeffrey K Trimmer William D Shrader |
| author_facet | Andrew Hinman Charles R Holst Joey C Latham Joel J Bruegger Gözde Ulas Kevin P McCusker Akiko Amagata Dana Davis Kevin G Hoff Amanda H Kahn-Kirby Virna Kim Yuko Kosaka Edgar Lee Stephanie A Malone Janet J Mei Steve James Richards Veronica Rivera Guy Miller Jeffrey K Trimmer William D Shrader |
| author_sort | Andrew Hinman |
| collection | DOAJ |
| description | Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity. |
| first_indexed | 2024-12-11T01:07:13Z |
| format | Article |
| id | doaj.art-1875891c4736481eb71993aa2c674781 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T01:07:13Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1875891c4736481eb71993aa2c6747812022-12-22T01:26:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01138e020136910.1371/journal.pone.0201369Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.Andrew HinmanCharles R HolstJoey C LathamJoel J BrueggerGözde UlasKevin P McCuskerAkiko AmagataDana DavisKevin G HoffAmanda H Kahn-KirbyVirna KimYuko KosakaEdgar LeeStephanie A MaloneJanet J MeiSteve James RichardsVeronica RiveraGuy MillerJeffrey K TrimmerWilliam D ShraderFerroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.http://europepmc.org/articles/PMC6093661?pdf=render |
| spellingShingle | Andrew Hinman Charles R Holst Joey C Latham Joel J Bruegger Gözde Ulas Kevin P McCusker Akiko Amagata Dana Davis Kevin G Hoff Amanda H Kahn-Kirby Virna Kim Yuko Kosaka Edgar Lee Stephanie A Malone Janet J Mei Steve James Richards Veronica Rivera Guy Miller Jeffrey K Trimmer William D Shrader Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS ONE |
| title | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. |
| title_full | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. |
| title_fullStr | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. |
| title_full_unstemmed | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. |
| title_short | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. |
| title_sort | vitamin e hydroquinone is an endogenous regulator of ferroptosis via redox control of 15 lipoxygenase |
| url | http://europepmc.org/articles/PMC6093661?pdf=render |
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