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A long-linker conjugate of fluorescein and triphenylphosphonium as mitochondria-targeted uncoupler and fluorescent neuro- and nephroprotector
- Source :
- Biochimica et biophysica acta. 1860(11 Pt)
- Publication Year :
- 2016
-
Abstract
- Background Limited uncoupling of oxidative phosphorylation is known to be beneficial in various laboratory models of diseases. Linking a triphenyl-phosphonium cation to fluorescein through a decyl (C 10 ) spacer yields a fluorescent uncoupler, coined mitoFluo, that selectively accumulates in energized mitochondria (Denisov et al., Chem.Commun. 2014). Methods Proton-transport activity of mitoFluo was tested in liposomes reconstituted with bacteriorhodopsin. To examine the uncoupling action on mitochondria, we monitored mitochondrial membrane potential in parallel with oxygen consumption. Neuro- and nephroprotecting activity was detected by a limb-placing test and a kidney ischemia/reperfusion protocol, respectively. Results We compared mitoFluo properties with those of its newly synthesized analog having a short (butyl) spacer (C 4 -mitoFluo). MitoFluo, but not C 4 -mitoFluo, caused collapse of mitochondrial membrane potential resulting in stimulation of mitochondrial respiration. The dramatic difference in the uncoupling activity of mitoFluo and C 4 -mitoFluo was in line with the difference in their protonophoric activity on a lipid membrane. The accumulation of mitoFluo in mitochondria was more pronounced than that of C 4 -mitoFluo . MitoFluo decreased the rate of ROS production in mitochondria. MitoFluo was effective in preventing consequences of brain trauma in rats: it suppressed trauma-induced brain swelling and reduced a neurological deficit. Besides, mitoFluo attenuated acute kidney injury after ischemia/reperfusion in rats. Conclusions A long alkyl linker was proved mandatory for mitoFluo to be a mitochondria- targeted uncoupler. MitoFluo showed high protective efficacy in certain models of oxidative stress-related diseases. General significance MitoFluo is a candidate for developing therapeutic and fluorescence imaging agents to treat brain and kidney pathologies.
- Subjects :
- 0301 basic medicine
Protonophore
Uncoupling Agents
Biophysics
Oxidative phosphorylation
Mitochondrion
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Onium Compounds
Organophosphorus Compounds
Animals
Fluorescein
Molecular Biology
Membrane potential
Liposome
030102 biochemistry & molecular biology
Chemistry
Onium compound
Mitochondria
Rats
030104 developmental biology
Neuroprotective Agents
Subjects
Details
- ISSN :
- 00063002
- Volume :
- 1860
- Issue :
- 11 Pt
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta
- Accession number :
- edsair.doi.dedup.....b2bac7d29fc08b70a3119552348d46ee