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Cited by 725Mitochondrial Function and PathologyCoenzyme Q10 studies and effectsNanoparticle-Based Drug Delivery

Delivery of bioactive molecules to mitochondria in vivo

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Smith, Robin A. J., Porteous, Carolyn M., Gane, Alison M., Murphy, Michael P.·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0931245100PMC PMC154358
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Abstract

Mitochondrial dysfunction contributes to many human degenerative diseases but specific treatments are hampered by the difficulty of delivering bioactive molecules to mitochondria in vivo . To overcome this problem we developed a strategy to target bioactive molecules to mitochondria by attachment to the lipophilic triphenylphosphonium cation through an alkyl linker. These molecules rapidly permeate lipid bilayers and, because of the large mitochondrial membrane potential (negative inside), accumulate several hundredfold inside isolated mitochondria and within mitochondria in cultured cells. To determine whether this strategy could lead to the development of mitochondria-specific therapies, we investigated the administration and tissue distribution in mice of simple alkyltriphenylphosphonium cations and of mitochondria-targeted antioxidants comprising a triphenylphosphonium cation coupled to a coenzyme Q or vitamin E derivative. Significant doses of these compounds could be fed safely to mice over long periods, coming to steady-state distributions within the heart, brain, liver, and muscle. Therefore, mitochondria-targeted bioactive molecules can be administered orally, leading to their accumulation at potentially therapeutic concentrations in those tissues most affected by mitochondrial dysfunction. This finding opens the way to the testing of mitochondria-specific therapies in mouse models of human degenerative diseases.

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Crossref · 10.1073/pnas.0931245100

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  • The quantity of TPP+ conjugated compound found within mitochondria can vary substantially between different cell types because uptake depends on plasma and mitochondrial membrane potential, incubation volume, cell volume, and number of mitochondria.

    “Because the extent of uptake of a TPP+ conjugated compound depends on the plasma and mitochondrial membrane potential, the volume of the incubation, the cell volume, and the number of mitochondria within a given cell, the quantity of the compound found within mitochondria can vary substantially between different cell types [18].”

    From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [18]

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Authors
Smith, R. A. J., Porteous, C. M., Gane, A. M., & Murphy, M. P.
Affiliations
MRC Mitochondrial Biology Unit (GB)
ORCID
Murphy, Michael P.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-04-15
Volume
100
Issue
9
Pages
5407-5412
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0931245100
PMC
PMC154358
OpenAlex
W2078265076
Cited by
725
References
6
Citations by year
2026: 27 · 2025: 34 · 2024: 39 · 2023: 30 · 2022: 40 · 2021: 37 · 2020: 47 · 2019: 42 · 2018: 44 · 2017: 49 · 2016: 37 · 2015: 40 · 2014: 38 · 2013: 29 · 2012: 23
FWCI
6.00
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
mitochondria-targeted drug delivery, triphenylphosphonium cation, alkyl linkers, mitochondrial membrane potential, mitochondrial dysfunction, mitochondria-targeted antioxidants, coenzyme Q10, vitamin E, tissue distribution, oral administration, degenerative diseases, mitochondrial therapeutics
MeSH terms
Animals, Animals, Newborn, Cations, Female, Fetus, Mitochondria, Liver, Mass Spectrometry, Tissue Distribution, Mice

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