Selective delivery of dicarboxylates to mitochondria by conjugation to a lipophilic cation via a cleavable linker

Prag, H. A., Kula-Alwar, D., Pala, L., Caldwell, S. T. , Beach, T. E., James, A. M., Saeb-Parsy, K., Krieg, T., Hartley, R. C. and Murphy, M. P. (2020) Selective delivery of dicarboxylates to mitochondria by conjugation to a lipophilic cation via a cleavable linker. Molecular Pharmaceutics, 17(9), pp. 3526-3540. (doi: 10.1021/acs.molpharmaceut.0c00533) (PMID:32692564) (PMCID:PMC7482397)

[img] Text
221191.pdf - Published Version
Available under License Creative Commons Attribution.

6MB
[img]
Preview
Text
221191Supp.pdf - Supplemental Material

1MB

Abstract

Many mitochondrial metabolites and bioactive molecules contain two carboxylic acid moieties that make them unable to cross biological membranes. Hence, there is considerable interest in facilitating the uptake of these molecules into cells and mitochondria, to modify or report on their function. Conjugation to the triphenylphosphonium (TPP) lipophilic cation is widely used to deliver molecules selectively to mitochondria in response to the membrane potential. However, permanent attachment to the cation can disrupt the biological function of small dicarboxylates. Here, we have developed a strategy using TPP to release dicarboxylates selectively within mitochondria. For this the dicarboxylate is attached to a TPP via a single ester bond which is then cleaved by intra-mitochondrial esterase activity, releasing the dicarboxylate within the organelle. Leaving the second carboxylic acid free also means mitochondrial uptake is dependent on the pH gradient across the inner membrane. To assess this strategy, we synthesized a range of TPP monoesters of the model dicarboxylate, malonate. We then tested their mitochondrial accumulation and ability to deliver malonate to isolated mitochondria, and to cells in vitro and in vivo. A TPP-malonate monoester, TPP11-malonate, in which the dicarboxylate was attached to the TPP via a hydrophobic undecyl link was most effective at releasing malonate within mitochondria in cells and in vivo. Therefore, we have developed a TPP-monoester platform that enables the selective release of bioactive dicarboxylates within mitochondria.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Pala, Ms Laura and Hartley, Professor Richard
Authors: Prag, H. A., Kula-Alwar, D., Pala, L., Caldwell, S. T., Beach, T. E., James, A. M., Saeb-Parsy, K., Krieg, T., Hartley, R. C., and Murphy, M. P.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Molecular Pharmaceutics
Publisher:American Chemical Society
ISSN:1543-8384
ISSN (Online):1543-8392
Published Online:21 July 2020
Copyright Holders:Copyright © 2020 American Chemical Society
First Published:First published in Molecular Pharmaceutics 17(9):3526–3540
Publisher Policy:Reproduced under a Creative Commons licence
Data DOI:10.5525/gla.researchdata.1031

University Staff: Request a correction | Enlighten Editors: Update this record