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Mitochondrial labile iron (LI) plays a crucial role in oxidative injuries and pathologies. At present, there is no organelle-specific sensitive iron sensor which can reside exclusively in the mitochondria and reliably monitor levels of LI in this organelle. Here we describe the development of novel fluorescent and highly specific mitochondria iron sensors, using the family of mitochondrial-homing ‘SS-peptides’ (short cell permeable signal peptides mimicking mitochondrial import sequence) as carriers of highly specific iron chelators for sensitive evaluation of the mitochondrial LI. Microscopy analysis of subcellular localization of a small library of fluorescently labelled SS-like peptides identified dansyl (DNS) as the lead fluorophore for the subsequent synthesis of chimeric iron chelator-peptides of either catechol (compound 10 and 11) or hydroxypyridinone (compounds 13 and 14) type. The iron-sensing ability of these chimeric compounds was confirmed by fluorescent quenching and de-quenching studies both in solution and in cells, with compound 13 exhibiting the highest sensitivity towards iron modulation. The intramolecular fluorophore-chelator distance and the iron affinity both influence probe sensitivity towards iron. These probes represent the first example of highly sensitive mitochondria-directed fluorescent iron chelators with significant potential to monitor mitochondrial LI level.
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