A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease
Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson’s disease (PD). Here we demonstrate the neu...
- Autores:
-
Fouché, Belinda
Turner, Stephanie
Gorham, Rebecca
Stephenson, Eloise J.
Gutbier, Simon
Elson, Joanna L.
García-Beltrán, Olimpo
Van Der Westhuizen, Francois H.
Pienaar, Ilse S.
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2023
- Institución:
- Universidad de Ibagué
- Repositorio:
- Repositorio Universidad de Ibagué
- Idioma:
- eng
- OAI Identifier:
- oai:repositorio.unibague.edu.co:20.500.12313/5572
- Acceso en línea:
- https://hdl.handle.net/20.500.12313/5572
https://link.springer.com/article/10.1007/s12035-022-03107-8
- Palabra clave:
- Mitocondría
Parkinson
Antioxidant
Iron chelation
Mitochondria; MPP+
Neuroprotection
Parkinson’s disease
- Rights
- closedAccess
- License
- http://purl.org/coar/access_right/c_14cb
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Repositorio Universidad de Ibagué |
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| dc.title.eng.fl_str_mv |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| title |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| spellingShingle |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease Mitocondría Parkinson Antioxidant Iron chelation Mitochondria; MPP+ Neuroprotection Parkinson’s disease |
| title_short |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| title_full |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| title_fullStr |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| title_full_unstemmed |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| title_sort |
A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease |
| dc.creator.fl_str_mv |
Fouché, Belinda Turner, Stephanie Gorham, Rebecca Stephenson, Eloise J. Gutbier, Simon Elson, Joanna L. García-Beltrán, Olimpo Van Der Westhuizen, Francois H. Pienaar, Ilse S. |
| dc.contributor.author.none.fl_str_mv |
Fouché, Belinda Turner, Stephanie Gorham, Rebecca Stephenson, Eloise J. Gutbier, Simon Elson, Joanna L. García-Beltrán, Olimpo Van Der Westhuizen, Francois H. Pienaar, Ilse S. |
| dc.subject.armarc.none.fl_str_mv |
Mitocondría Parkinson |
| topic |
Mitocondría Parkinson Antioxidant Iron chelation Mitochondria; MPP+ Neuroprotection Parkinson’s disease |
| dc.subject.proposal.eng.fl_str_mv |
Antioxidant Iron chelation Mitochondria; MPP+ Neuroprotection Parkinson’s disease |
| description |
Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson’s disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). MPP+’s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug’s interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent |
| publishDate |
2023 |
| dc.date.issued.none.fl_str_mv |
2023-02 |
| dc.date.accessioned.none.fl_str_mv |
2025-08-29T22:33:04Z |
| dc.date.available.none.fl_str_mv |
2025-08-29T22:33:04Z |
| dc.type.none.fl_str_mv |
Artículo de revista |
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http://purl.org/coar/resource_type/c_2df8fbb1 |
| dc.type.coarversion.none.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.content.none.fl_str_mv |
Text |
| dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/article |
| dc.type.version.none.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| format |
http://purl.org/coar/resource_type/c_2df8fbb1 |
| status_str |
publishedVersion |
| dc.identifier.citation.none.fl_str_mv |
Fouché, B., Turner, S., Gorham, R., Stephenson, E., Gutbier, S., Elson, J., García-Beltrán, O., Van Der Westhuizen, F. y Pienaar, I. (2023). A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease. Molecular Neurobiology, 60(2), 749 - 767. DOI: 10.1007/s12035-022-03107-8 |
| dc.identifier.doi.none.fl_str_mv |
10.1007/s12035-022-03107-8 |
| dc.identifier.eissn.none.fl_str_mv |
15591182 |
| dc.identifier.issn.none.fl_str_mv |
08937648 |
| dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/20.500.12313/5572 |
| dc.identifier.url.none.fl_str_mv |
https://link.springer.com/article/10.1007/s12035-022-03107-8 |
| identifier_str_mv |
Fouché, B., Turner, S., Gorham, R., Stephenson, E., Gutbier, S., Elson, J., García-Beltrán, O., Van Der Westhuizen, F. y Pienaar, I. (2023). A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease. Molecular Neurobiology, 60(2), 749 - 767. DOI: 10.1007/s12035-022-03107-8 10.1007/s12035-022-03107-8 15591182 08937648 |
| url |
https://hdl.handle.net/20.500.12313/5572 https://link.springer.com/article/10.1007/s12035-022-03107-8 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.citationendpage.none.fl_str_mv |
767 |
| dc.relation.citationissue.none.fl_str_mv |
2 |
| dc.relation.citationstartpage.none.fl_str_mv |
749 |
| dc.relation.citationvolume.none.fl_str_mv |
60 |
| dc.relation.ispartofjournal.none.fl_str_mv |
Molecular Neurobiology |
| dc.relation.references.none.fl_str_mv |
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Fouché, Belindafcc113fb-1061-4ae2-904b-62cd1054ed67-1Turner, Stephanie0dafe24d-904d-4e3a-82ec-eb646a72d7fc-1Gorham, Rebeccadb8132bc-debf-411d-9be4-d3b079903d0b-1Stephenson, Eloise J.c7f27bc9-6463-4295-a403-27465d12d7d3-1Gutbier, Simonf6cefc73-1da0-4436-b0a3-8bcfa067a545-1Elson, Joanna L.a15b77d6-bae6-4dba-8e03-e12009f7d0f0-1García-Beltrán, Olimpo5bc12f58-2b62-4c7c-a477-0820b4de72e9-1Van Der Westhuizen, Francois H.5307774c-fc85-4f81-90f7-a89460c37e9c-1Pienaar, Ilse S.4dcd4d53-71c6-4202-befe-6356390d6ea2-12025-08-29T22:33:04Z2025-08-29T22:33:04Z2023-02Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson’s disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). MPP+’s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug’s interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agentapplication/pdfFouché, B., Turner, S., Gorham, R., Stephenson, E., Gutbier, S., Elson, J., García-Beltrán, O., Van Der Westhuizen, F. y Pienaar, I. (2023). A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease. Molecular Neurobiology, 60(2), 749 - 767. DOI: 10.1007/s12035-022-03107-810.1007/s12035-022-03107-81559118208937648https://hdl.handle.net/20.500.12313/5572https://link.springer.com/article/10.1007/s12035-022-03107-8engSpringerEstados Unidos767274960Molecular NeurobiologyLyons TJ, Eide DJ (2007) Transport and storage of metal ions in biology. In: Bertini I, Gray HB, Stiefel EI, Valentine JS (eds) Biological Inorganic Chemistry. 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EMBO Rep 21:e50202© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.info:eu-repo/semantics/closedAccesshttp://purl.org/coar/access_right/c_14cbAtribución-NoComercial 4.0 Internacional (CC BY-NC 4.0)https://creativecommons.org/licenses/by-nc/4.0/https://pubmed.ncbi.nlm.nih.gov/36357615/MitocondríaParkinsonAntioxidantIron chelationMitochondria; MPP+NeuroprotectionParkinson’s diseaseA Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s DiseaseArtículo de revistahttp://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/coar/version/c_970fb48d4fbd8a85Textinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionPublicationLICENSElicense.txtlicense.txttext/plain; charset=utf-8134https://repositorio.unibague.edu.co/bitstreams/f00563bd-98ed-4d9d-9a74-d66d3e0ddc18/download2fa3e590786b9c0f3ceba1b9656b7ac3MD51TEXTArtículo.pdf.txtArtículo.pdf.txtExtracted texttext/plain4203https://repositorio.unibague.edu.co/bitstreams/4e96fd68-32d5-4e53-95a0-704169c39ed6/download7600b88503ea92ec84ea3d2eb09d6d6cMD53THUMBNAILArtículo.pdf.jpgArtículo.pdf.jpgIM Thumbnailimage/jpeg24229https://repositorio.unibague.edu.co/bitstreams/221e1c4b-0cad-41c7-a28d-c07a7464659d/download08da6115c49ff8ff9d9314e80d189848MD54ORIGINALArtículo.pdfArtículo.pdfapplication/pdf140394https://repositorio.unibague.edu.co/bitstreams/abd69c66-9cf6-427d-b1fd-462914412bb1/downloadd3011a0ed8ca49864119263f5bdbe0f7MD5220.500.12313/5572oai:repositorio.unibague.edu.co:20.500.12313/55722025-09-12 12:24:02.672https://creativecommons.org/licenses/by-nc/4.0/© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.https://repositorio.unibague.edu.coRepositorio Institucional Universidad de Ibaguébdigital@metabiblioteca.comQ3JlYXRpdmUgQ29tbW9ucyBBdHRyaWJ1dGlvbi1Ob25Db21tZXJjaWFsLU5vRGVyaXZhdGl2ZXMgNC4wIEludGVybmF0aW9uYWwgTGljZW5zZQ0KaHR0cHM6Ly9jcmVhdGl2ZWNvbW1vbnMub3JnL2xpY2Vuc2VzL2J5LW5jLW5kLzQuMC8= |