Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Metallomics. 2019 Mar 20;11(3):656-665. doi: 10.1039/c8mt00257f.
Mitochondrial labile iron (LI) is a major contributor to the susceptibility of skin fibroblasts to ultraviolet A (UVA)-induced oxidative damage leading to necrotic cell death via ATP depletion. Mitochondria iron overload is a key feature of the neurodegenerative disease Friedreich's ataxia (FRDA). Here we show that cultured primary skin fibroblasts from FRDA patients are 4 to 10-fold more sensitive to UVA-induced death than their healthy counterparts. We demonstrate that FRDA cells display higher levels of mitochondrial LI (up to 6-fold on average compared to healthy counterparts) and show higher increase in mitochondrial reactive oxygen species (ROS) generation after UVA irradiation (up to 2-fold on average), consistent with their differential sensitivity to UVA. Pre-treatment of the FRDA cells with a bespoke mitochondrial iron chelator fully abrogates the UVA-mediated cell death and reduces UVA-induced damage to mitochondrial membrane and the resulting ATP depletion by a factor of 2. Our results reveal a link between FRDA as a disease of mitochondrial iron overload and sensitivity to UVA of skin fibroblasts. Our findings suggest that the high levels of mitochondrial LI in FRDA cells which contribute to high levels of mitochondrial ROS production after UVA irradiation are likely to play a crucial role in the marked sensitivity of these cells to UVA-induced oxidative damage. This study may have implications not only for FRDA but also for other diseases of mitochondrial iron overload, with the view to develop topical mitochondria-targeted iron chelators as skin photoprotective agents.
线粒体不稳定铁（LI）是导致皮肤成纤维细胞对紫外线 A（UVA）诱导的氧化损伤敏感的主要因素之一，通过 ATP 耗竭导致坏死性细胞死亡。线粒体铁过载是弗里德里希共济失调（FRDA）神经退行性疾病的一个关键特征。在这里，我们显示 FRDA 患者的培养原代皮肤成纤维细胞比健康对照组对 UVA 诱导的死亡敏感 4 到 10 倍。我们证明 FRDA 细胞显示更高水平的线粒体 LI（与健康对照组相比平均高达 6 倍），并且在 UVA 照射后显示更高的线粒体活性氧（ROS）生成增加（平均高达 2 倍），与它们对 UVA 的差异敏感性一致。用定制的线粒体铁螯合剂预处理 FRDA 细胞可完全消除 UVA 介导的细胞死亡，并将 UVA 诱导的线粒体膜损伤和由此产生的 ATP 耗竭减少 2 倍。我们的结果揭示了 FRDA 作为一种线粒体铁过载疾病与皮肤成纤维细胞对 UVA 的敏感性之间的联系。我们的发现表明，FRDA 细胞中线粒体 LI 水平高，这导致 UVA 照射后线粒体 ROS 生成水平高，这可能在这些细胞对 UVA 诱导的氧化损伤的高敏感性中发挥关键作用。这项研究不仅对 FRDA，而且对其他线粒体铁过载疾病都具有重要意义，以期开发针对线粒体的局部铁螯合剂作为皮肤光保护剂。
