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Pala L, Senn HM, Caldwell ST, et al. Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation. Front Chem. 2020;8:783doi: 10.3389/fchem.2020.00783.
Pala, L., Senn, H. M., Caldwell, S. T., Prime, T. A., Warrington, S., Bright, T. P., Prag, H. A., Wilson, C., Murphy, M. P., & Hartley, R. C. (2020). Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation. Frontiers in chemistry, 8783. https://doi.org/10.3389/fchem.2020.00783
Pala, Laura, et al. "Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation." Frontiers in chemistry vol. 8 (2020): 783. doi: https://doi.org/10.3389/fchem.2020.00783
Pala L, Senn HM, Caldwell ST, Prime TA, Warrington S, Bright TP, Prag HA, Wilson C, Murphy MP, Hartley RC. Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation. Front Chem. 2020 Sep 09;8:783. doi: 10.3389/fchem.2020.00783. eCollection 2020. PMID: 33033715; PMCID: PMC7509049.
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Front Chem. 2020 Sep 09;8:783. doi: 10.3389/fchem.2020.00783. eCollection 2020.

Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation.

Frontiers in chemistry

Laura Pala, Hans M Senn, Stuart T Caldwell, Tracy A Prime, Stefan Warrington, Thomas P Bright, Hiran A Prag, Claire Wilson, Michael P Murphy, Richard C Hartley

Affiliations

  1. School of Chemistry, University of Glasgow, Glasgow, United Kingdom.
  2. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
  3. Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

PMID: 33033715 PMCID: PMC7509049 DOI: 10.3389/fchem.2020.00783

Abstract

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 pK

Copyright © 2020 Pala, Senn, Caldwell, Prime, Warrington, Bright, Prag, Wilson, Murphy and Hartley.

Keywords: computational chemistry; membrane permeation; membrane potential; mitochondria; mitochondria-targeting; pH gradient; phosphonium

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