Delivery of bioactive molecules to mitochondria in vivo.

TitleDelivery of bioactive molecules to mitochondria in vivo.
Publication TypeJournal Article
Year of Publication2003
AuthorsSmith, RAJ, Porteous, CM, Gane, AM, Murphy, MP
JournalProc Natl Acad Sci U S A
Volume100
Issue9
Pagination5407-12
Date Published2003 Apr 29
ISSN0027-8424
KeywordsAnimals, Animals, Newborn, Cations, Female, Fetus, Mass Spectrometry, Mice, Mitochondria, Liver, Tissue Distribution
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.

DOI10.1073/pnas.0931245100
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.0931245100
PubMed ID12697897
PubMed Central IDPMC154358