Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: implications for mitochondria-specific therapies and probes.
BACKGROUND
Mitochondrial dysfunction contributes to a range of pathologies, consequently there is a need to monitor mitochondrial function and to intervene pharmacologically to prevent mitochondrial damage. One approach to this is to deliver antioxidants, probes and pharmacophores to mitochondria by conjugation to the lipophilic triphenylphosphonium (TPP) cation that is taken up selectively by mitochondria driven by the membrane potential.


CONCLUSIONS
Oral administration of TPP-conjugated antioxidants protects against mitochondrial damage in vivo. However, there is also a need to deliver molecules rapidly to mitochondria to respond quickly to pathologies and for the real-time assessment of mitochondrial function.


METHODS
To see if this was possible we investigated how rapidly TPP cations were taken up by mitochondria in vivo following intravenous (iv) administration.


RESULTS
AlkylTPP cations were accumulated selectively by mitochondria within mice within 5 min of iv injection. The extent of uptake was enhanced 10-30-fold relative to simple alkylTPP cations by attaching functional groups to the TPP cation via long, hydrophobic alkyl chains. Conclusions: Mitochondria-targeted antioxidants, probes and pharmacophores can be delivered into mitochondria within minutes of iv administration.


CONCLUSIONS
These findings greatly extend the utility of mitochondria-targeted lipophilic cations as therapies and probes.
Porteous
Carolyn M
CM
Department of Chemistry, University of Otago, Dunedin 9054, New Zealand.
Logan
Angela
A
Evans
Cameron
C
Ledgerwood
Elizabeth C
EC
Menon
David K
DK
Aigbirhio
Franklin
F
Smith
Robin A J
RA
Murphy
Michael P
MP
D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics* / Q000494:pharmacology; D002412:Cations; D016503:Drug Delivery Systems; D005260:Female; D007275:Injections, Intravenous; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology
D000975:Antioxidants; D002412:Cations; D009943:Organophosphorus Compounds