A Powerful Mitochondria-Targeted Iron Chelator Affords High Photoprotection against Solar Ultraviolet A Radiation

Olivier Reelfs,Vincenzo Abbate,Robert C Hider,Charareh Pourzand

doi:10.1016/j.jid.2016.03.041

Olivier Reelfs, Vincenzo Abbate + Show 2 more

Open Access

https://doi.org/10.1016/j.jid.2016.03.041

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Abstract

Mitochondria are the principal destination for labile iron, making these organelles particularly susceptible to oxidative damage on exposure to ultraviolet A (UVA, 320–400 nm), the oxidizing component of sunlight. The labile iron-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via adenosine triphosphate depletion. Therefore, targeted removal of mitochondrial labile iron via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria-homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, adenosine triphosphate depletion, and the ensuing necrotic cell death in skin fibroblasts, and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of the UVA component of sunlight.

Highlights

The ultraviolet A (UVA, 320e400 nm) component of sunlight is weakly absorbed by most biomolecules but is predominantly oxidative in nature, generating reactive oxygen species (ROS) via photochemical interactions involving non-DNA cellular chromophores (Tyrrell, 1996)
We have shown that UVA radiation or H2O2 treatment of human skin fibroblasts and Jurkat T leukemia cell line in culture leads to both immediate oxidative damage to mitochondrial membrane and a concomitant rise in the cytosolic labile iron pool (LIP) (Al-Qenaei et al, 2014; Yiakouvaki et al, 2006; Zhong et al, 2004)
The same subcellular pattern of localization was observed for compound 3 using FCP7, which we have previously studied in our laboratory (Zhong et al, 2004)

Summary

Introduction

The ultraviolet A (UVA, 320e400 nm) component of sunlight is weakly absorbed by most biomolecules but is predominantly oxidative in nature, generating reactive oxygen species (ROS) via photochemical interactions involving non-DNA cellular chromophores (Tyrrell, 1996). The presence of a cellular pool of iron bound to small ligands, called labile iron pool (LIP), sensitizes cells to UVA as it can catalyze the formation of toxic oxygen-containing radicals (Cabantchik, 2014, Hider and Kong, 2013) such as hydroxyl radical (OH) via Fenton chemistry (Winterbourn, 2008). This can overwhelm the cellular antioxidant defense mechanisms and lead to cell damage and death (Ma et al, 2015, Reelfs et al, 2004, 2010).

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