A Novel Triphenylphosphonium Carrier to Target Mitochondria without Uncoupling Oxidative Phosphorylation
- 4 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (1), 662-676
- https://doi.org/10.1021/acs.jmedchem.0c01671
Abstract
Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria is a powerful approach to study and treat these diseases. The triphenylphosphonium (TPP+) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP+ is not inert; TPP+ conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP+-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP+ phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP+ moiety and prevent dissipation of mitochondrial membrane potential. These alterations of the TPP+ structure do not negatively affect the delivery of cargo to mitochondria. Results here identify the 4-CF3-phenyl TPP+ moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.Keywords
Funding Information
- U.S. Department of Veterans Affairs (2 I01 BX000285-05)
- American Heart Association (19POST34380212)
- University of Iowa
- Iowa State Fraternal Order of the Eagles
- College of Pharmacy, University of Iowa
This publication has 38 references indexed in Scilit:
- Peptide-Mediated Delivery of Chemical Probes and Therapeutics to MitochondriaAccounts of Chemical Research, 2016
- Mitochondria: In Sickness and in HealthCell, 2012
- Animal and human studies with the mitochondria‐targeted antioxidant MitoQAnnals of the New York Academy of Sciences, 2010
- Roles of mitochondria in human diseaseEssays in Biochemistry, 2010
- Mitochondria as a target in treatmentEnvironmental and Molecular Mutagenesis, 2010
- Targeting lipophilic cations to mitochondriaBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2008
- Targeting MitochondriaAccounts of Chemical Research, 2008
- Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic CationsAnnual Review of Pharmacology and Toxicology, 2007
- Mitochondrial dysfunction and oxidative stress in neurodegenerative diseasesNature, 2006
- Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biologyBiochemistry (Moscow), 2005