Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: Implications for mitochondria-specific therapies and probes

被引：101

作者：

Porteous, Carolyn M. ^{[2
,3
]}

Logan, Angela ^{[1
]}

Evans, Cameron ^{[2
]}

Ledgerwood, Elizabeth C. ^{[3
]}

Menon, David K. ^{[4
]}

Aigbirhio, Franklin ^{[5
]}

Smith, Robin A. J. ^{[2
]}

Murphy, Michael P. ^{[1
]}

机构：

[1] MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England

[2] Univ Otago, Dept Chem, Dunedin 9054, New Zealand

[3] Univ Otago, Dept Biochem, Dunedin 9054, New Zealand

[4] Univ Cambridge, Addenbrookes Hosp, Div Anaesthesia, Cambridge CB2 0QQ, England

[5] Univ Cambridge, Addenbrookes Hosp, Wolfson Brain Imaging Ctr, Dept Clin Neurosci, Cambridge CB2 0QQ, England

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 2010年 / 1800卷 / 09期

基金：

英国医学研究理事会;

关键词：

Mitochondrion; Antioxidant; MitoQ; Phosphonium cation; Oxidative stress; ISCHEMIA-REPERFUSION INJURY; DEPMPO SPIN TRAP; TARGETED ANTIOXIDANT; LIVING CELLS; PHOSPHONIUM; SUPEROXIDE; DAMAGE; APOPTOSIS; PEROXIDE; PROTECTS;

D O I：

10.1016/j.bbagen.2010.06.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. General significance: These findings greatly extend the utility of mitochondria-targeted lipophilic cations as therapies and probes. (C) 2010 Elsevier B.V. All rights reserved.

引用

页码：1009 / 1017

页数：9