Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases

Seibel, Peter; Trappe, Jörg; Villani, Gaetano; Klopstock, Thomas; Papa, Sergio; Reichmann, Heinz

doi:10.1093/nar/23.1.10

Cited by 156 publications

(74 citation statements)

References 46 publications

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“…Vestweber and Schatz, 28 however, were able to demonstrate that by subjecting import-competent, isolated mitochondria to DNA-conjugated mitochondrial precursor proteins, the DNA became nuclease or phosphodiesterase resistant, consistent with the mitochondria importing nucleic acids via the general protein import pathway. A similar observation was more recently reported by Seibel et al, 29 although their experiments involved a less direct analysis of the putatively imported DNA moiety. Our in vitro studies with isolated rat liver mitochondria now show that biotinylated PNAs can also be delivered across an intact mitochondrial membrane into the matrix compartment by the addition of a mitochondrial targeting peptide.…”

Section: Mitochondrial Targeting and Importsupporting

confidence: 87%

Peptide nucleic acid delivery to human mitochondria

et al. 1999

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Peptide nucleic acids (PNAs) are synthetic polynucleobase as therapeutic agents for mtDNA disease, we attempted to molecules, which bind to DNA and RNA with high affinity localise PNAs to the mitochondrial matrix. When attached and specificity. Although PNAs have enormous potential to the presequence peptide of the nuclear-encoded human as anti-sense agents, the success of PNA-mediated gene cytochrome c oxidase (COX) subunit VIII, the biotinylated therapy will require efficient cellular uptake and sub-cellular PNA was successfully imported into isolated organelles in trafficking. At present these mechanisms are poorly undervitro. Furthermore, delivery of the biotinylated peptide-PNA stood. To address this, we have studied the uptake of biotito mitochondria in intact cells was confirmed by confocal nylated PNAs into cultured cell lines using fluorescence microscopy. These studies demonstrate that biotinylated confocal microscopy. In human myoblasts, initial punctate PNAs can be directed across cell membranes and to a staining was followed by the release of PNAs into the cytospecific sub-cellular compartment within human cellssol and subsequent localisation and concentration in the highlighting the importance of these novel molecules for nucleus. To determine whether PNAs could also be used human gene therapy.

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Section: Mitochondrial Targeting and Importsupporting

confidence: 87%

Peptide nucleic acid delivery to human mitochondria

et al. 1999

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“…This approach enables a range of small molecules to be targeted to mitochondria and extends and complements earlier approaches designed to target DNA and related molecules to mitochondria (39)(40)(41). For this strategy to have clinical potential, therapeutically effective concentrations of bioactive molecules must be delivered to mitochondria without toxicity.…”

Section: Discussionmentioning

confidence: 94%

Delivery of bioactive molecules to mitochondria in vivo

Smith

Porteous

Gane

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

665

539

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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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“…Previous reports showed that the conjugation or direct modification of MTS permitted a macromolecule such as a protein, DNA and a liposomal nanocarrier to be delivered to mitochondria [8][9][10][11][12] . On the other hand, some researchers have reported the use of a mitochondrial RNA aptamer for mitochondrial delivery.…”

Section: Introductionmentioning

confidence: 99%