Toxicity of blue led light and A2E is associated to mitochondrial dynamics impairment in ARPE-19 cells: implications for age-related macular degeneration
Toxicity of blue led light and A2E is associated to mitochondrial dynamics impairment in ARPE-19 cells: implications for age-related macular degeneration
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DOI：
10.1007/s00204-019-02409-6
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发表时间：
2019-05-01
影响因子：
6.1
通讯作者：
Lidia Kotler, Monica
中科院分区：
文献类型：
--
作者：
Alaimo, Agustina;Garcia Linares, Guadalupe;Lidia Kotler, Monica
年龄相关性黄斑变性（AMD）是一种多因素视网膜疾病，其特征是中心视力的进行性丧失。视网膜色素上皮（RPE）变性是AMD的关键事件。它与A2E积累有关，A2E积累使RPE对蓝光光损伤敏感。线粒体质量控制机制已经发展到确保线粒体完整性和保持细胞稳态。特别是，线粒体动力学涉及线粒体裂变和融合的调节，以保持一个健康的线粒体网络。本研究旨在阐明光损伤诱导RPE细胞死亡的细胞和分子机制，特别关注线粒体动力学缺陷的参与。发光二极管辐照（445 +/- 18 nm; 4.43 mW/cm(2)）显著降低了未加载和加载a2e的人ARPE-19细胞的活力，并增加了活性氧的产生。MC540/ pi流式细胞术检测A2E和蓝光作用下细胞凋亡，并激活caspase-3。蓝光诱导无负载和a2e负载细胞的线粒体融合/裂变失衡，导致线粒体分裂，这与线粒体形成蛋白（OPA1， DRP1和OMA1）水平的失调有关。据我们所知，这是首次报道光损伤导致RPE细胞线粒体动力学失调。这一过程可能导致AMD的病理变化。我们的研究结果表明，线粒体动力学的调节可能是治疗视网膜变性疾病（如AMD）的一种有价值的策略。
Age-related macular degeneration (AMD) is a multifactorial retinal disease characterized by a progressive loss of central vision. Retinal pigment epithelium (RPE) degeneration is a critical event in AMD. It has been associated to A2E accumulation, which sensitizes RPE to blue light photodamage. Mitochondrial quality control mechanisms have evolved to ensure mitochondrial integrity and preserve cellular homeostasis. Particularly, mitochondrial dynamics involve the regulation of mitochondrial fission and fusion to preserve a healthy mitochondrial network. The present study aims to clarify the cellular and molecular mechanisms underlying photodamage-induced RPE cell death with particular focus on the involvement of defective mitochondrial dynamics. Light-emitting diodes irradiation (445 +/- 18 nm; 4.43 mW/cm(2)) significantly reduced the viability of both unloaded and A2E-loaded human ARPE-19 cells and increased reactive oxygen species production. A2E along with blue light, triggered apoptosis measured by MC540/PI-flow cytometry and activated caspase-3. Blue light induced mitochondrial fusion/fission imbalance towards mitochondrial fragmentation in both non-loaded and A2E-loaded cells which correlated with the deregulation of mitochondria-shaping proteins level (OPA1, DRP1 and OMA1). To our knowledge, this is the first work reporting that photodamage causes mitochondrial dynamics deregulation in RPE cells. This process could possibly contribute to AMD pathology. Our findings suggest that the regulation of mitochondrial dynamics may be a valuable strategy for treating retinal degeneration diseases, such as AMD.