Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, Shaanxi 710032, China; Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, Shaanxi 710032, China.
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, Shaanxi 710032, China.
J Dermatol Sci. 2019 Oct;96(1):33-41. doi: 10.1016/j.jdermsci.2019.09.001. Epub 2019 Sep 6.
Reactive oxygen species (ROS)-induced mitochondrial damage aggravates oxidative stress and activates mitochondrial apoptosis pathway to mediate melanocyte death. However, the repair mechanisms underlying damaged mitochondria of melanocytes remain unclear. Accumulative evidence has revealed that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a vital role in maintaining mitochondrial homeostasis.
To investigate whether the AHR signaling pathway could protect human melanocytes from oxidative damage through controlling mitochondrial quality.
We constructed an oxidative stress model of melanocytes with hydrogen peroxide (HO) in the human normal melanocyte PIG1 cell line, and detected ROS level, apoptosis, mitochondrial ROS level, mitochondrial membrane potential, ATP production, mitochondrial DNA and mitochondrial modulators after co-treatment with AHR ligand or antagonist and HO in the PIG1 cells.
In the present study, we found that HO-induced oxidative stress directly activated the AHR signaling pathway in melanocytes, whereas abnormal activation of AHR signaling pathway enhanced oxidative damage to mitochondria and melanocytes. Further studies showed that the AHR signaling pathway promoted mitochondrial DNA synthesis and ATP production probably by regulating the expression of nuclear respiratory factor 1 (NRF1) and its downstream targets.
Our findings reveal that the AHR signaling pathway might have a major role in protecting melanocytes against oxidative damage via inducing mitochondrial biogenesis, while impaired AHR activation could cause defective repair of mitochondria and exacerbate oxidative damage-induced apoptosis in melanocytes. Our data suggest that the AHR signaling pathway might be a novel mechanism of mitochondrial biogenesis involved in protecting melanocytes from oxidative stress.
活性氧（ROS）诱导的线粒体损伤加剧氧化应激，激活线粒体凋亡途径，介导黑素细胞死亡。然而，黑素细胞受损线粒体的修复机制尚不清楚。累积的证据表明，芳香烃受体（AHR）是一种配体激活的转录因子，在维持线粒体稳态方面发挥着重要作用。
探讨 AHR 信号通路是否可以通过控制线粒体质量来保护人黑素细胞免受氧化损伤。
我们在人正常黑素细胞 PIG1 细胞系中用过氧化氢（HO）构建了黑素细胞氧化应激模型，并在 PIG1 细胞中用 AHR 配体或拮抗剂与 HO 共同处理后，检测 ROS 水平、凋亡、线粒体 ROS 水平、线粒体膜电位、ATP 生成、线粒体 DNA 和线粒体调节剂。
在本研究中，我们发现 HO 诱导的氧化应激直接激活了黑素细胞中的 AHR 信号通路，而 AHR 信号通路的异常激活增强了线粒体和黑素细胞的氧化损伤。进一步的研究表明，AHR 信号通路可能通过调节核呼吸因子 1（NRF1）及其下游靶基因的表达来促进线粒体 DNA 合成和 ATP 生成。
我们的研究结果表明，AHR 信号通路可能通过诱导线粒体生物发生来保护黑素细胞免受氧化应激，而受损的 AHR 激活可能导致线粒体修复缺陷，并加剧氧化应激诱导的黑素细胞凋亡。我们的数据表明，AHR 信号通路可能是一种参与保护黑素细胞免受氧化应激的线粒体生物发生的新机制。
