Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation
There is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules...
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| Format: | Article |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2020.00783/full |
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| author | Laura Pala Hans M. Senn Stuart T. Caldwell Tracy A. Prime Stefan Warrington Thomas P. Bright Hiran A. Prag Claire Wilson Michael P. Murphy Michael P. Murphy Richard C. Hartley |
| author_facet | Laura Pala Hans M. Senn Stuart T. Caldwell Tracy A. Prime Stefan Warrington Thomas P. Bright Hiran A. Prag Claire Wilson Michael P. Murphy Michael P. Murphy Richard C. Hartley |
| author_sort | Laura Pala |
| collection | DOAJ |
| description | There is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules conjugated to lipophilic phosphonium cations to the organelle. Due to their combination of charge and hydrophobicity, quaternary triarylphosphonium cations rapidly cross biological membranes without the requirement for a carrier. Their extent of uptake is determined by the magnitude of the mitochondrial membrane potential, as described by the Nernst equation. To further enhance this uptake here we explored whether incorporation of a carboxylic acid into a quaternary triarylphosphonium cation would enhance its mitochondrial uptake in response to both the membrane potential and the mitochondrial pH gradient (alkaline inside). Accumulation of arylpropionic acid derivatives depended on both the membrane potential and the pH gradient. However, acetic or benzoic derivatives did not accumulate, due to their lowered pKa. Surprisingly, despite not being taken up by mitochondria, the phenylacetic or phenylbenzoic derivatives were not retained within mitochondria when generated within the mitochondrial matrix by hydrolysis of their cognate esters. Computational studies, supported by crystallography, showed that these molecules passed through the hydrophobic core of mitochondrial inner membrane as a neutral dimer. This finding extends our understanding of the mechanisms of membrane permeation of lipophilic cations and suggests future strategies to enhance drug and probe delivery to mitochondria. |
| first_indexed | 2024-12-10T21:21:14Z |
| format | Article |
| id | doaj.art-55f3b6d8361e43d484624302dfb0660e |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-10T21:21:14Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-55f3b6d8361e43d484624302dfb0660e2022-12-22T01:33:07ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-09-01810.3389/fchem.2020.00783556276Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid IncorporationLaura Pala0Hans M. Senn1Stuart T. Caldwell2Tracy A. Prime3Stefan Warrington4Thomas P. Bright5Hiran A. Prag6Claire Wilson7Michael P. Murphy8Michael P. Murphy9Richard C. Hartley10School of Chemistry, University of Glasgow, Glasgow, United KingdomSchool of Chemistry, University of Glasgow, Glasgow, United KingdomSchool of Chemistry, University of Glasgow, Glasgow, United KingdomMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United KingdomSchool of Chemistry, University of Glasgow, Glasgow, United KingdomMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United KingdomMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United KingdomSchool of Chemistry, University of Glasgow, Glasgow, United KingdomMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United KingdomDepartment of Medicine, University of Cambridge, Cambridge, United KingdomSchool of Chemistry, University of Glasgow, Glasgow, United KingdomThere is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules conjugated to lipophilic phosphonium cations to the organelle. Due to their combination of charge and hydrophobicity, quaternary triarylphosphonium cations rapidly cross biological membranes without the requirement for a carrier. Their extent of uptake is determined by the magnitude of the mitochondrial membrane potential, as described by the Nernst equation. To further enhance this uptake here we explored whether incorporation of a carboxylic acid into a quaternary triarylphosphonium cation would enhance its mitochondrial uptake in response to both the membrane potential and the mitochondrial pH gradient (alkaline inside). Accumulation of arylpropionic acid derivatives depended on both the membrane potential and the pH gradient. However, acetic or benzoic derivatives did not accumulate, due to their lowered pKa. Surprisingly, despite not being taken up by mitochondria, the phenylacetic or phenylbenzoic derivatives were not retained within mitochondria when generated within the mitochondrial matrix by hydrolysis of their cognate esters. Computational studies, supported by crystallography, showed that these molecules passed through the hydrophobic core of mitochondrial inner membrane as a neutral dimer. This finding extends our understanding of the mechanisms of membrane permeation of lipophilic cations and suggests future strategies to enhance drug and probe delivery to mitochondria.https://www.frontiersin.org/article/10.3389/fchem.2020.00783/fullmitochondriaphosphoniummitochondria-targetingmembrane permeationmembrane potentialpH gradient |
| spellingShingle | Laura Pala Hans M. Senn Stuart T. Caldwell Tracy A. Prime Stefan Warrington Thomas P. Bright Hiran A. Prag Claire Wilson Michael P. Murphy Michael P. Murphy Richard C. Hartley Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation Frontiers in Chemistry mitochondria phosphonium mitochondria-targeting membrane permeation membrane potential pH gradient |
| title | Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation |
| title_full | Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation |
| title_fullStr | Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation |
| title_full_unstemmed | Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation |
| title_short | Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation |
| title_sort | enhancing the mitochondrial uptake of phosphonium cations by carboxylic acid incorporation |
| topic | mitochondria phosphonium mitochondria-targeting membrane permeation membrane potential pH gradient |
| url | https://www.frontiersin.org/article/10.3389/fchem.2020.00783/full |
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