Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; University of Debrecen, Doctoral School of Health Sciences, 4032, Debrecen, Hungary.
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
Redox Biol. 2021 Jan;38:101808. doi: 10.1016/j.redox.2020.101808. Epub 2020 Nov 25.
Ultraviolet B radiation (UVB) is an environmental complete carcinogen, which induces and promotes keratinocyte carcinomas, the most common human malignancies. UVB induces the formation of cyclobutane pyrimidine dimers (CPDs). Repairing CPDs through nucleotide excision repair is slow and error-prone in placental mammals. In addition to the mutagenic and malignancy-inducing effects, UVB also elicits poorly understood complex metabolic changes in keratinocytes, possibly through CPDs. To determine the effects of CPDs, CPD-photolyase was overexpressed in keratinocytes using an N1-methyl pseudouridine-containing in vitro-transcribed mRNA. CPD-photolyase, which is normally not present in placental mammals, can efficiently and rapidly repair CPDs to block signaling pathways elicited by CPDs. Keratinocytes surviving UVB irradiation turn hypermetabolic. We show that CPD-evoked mitochondrial reactive oxygen species production, followed by the activation of several energy sensor enzymes, including sirtuins, AMPK, mTORC1, mTORC2, p53, and ATM, is responsible for the compensatory metabolic adaptations in keratinocytes surviving UVB irradiation. Compensatory metabolic changes consist of enhanced glycolytic flux, Szent-Györgyi-Krebs cycle, and terminal oxidation. Furthermore, mitochondrial fusion, mitochondrial biogenesis, and lipophagy characterize compensatory hypermetabolism in UVB-exposed keratinocytes. These properties not only support the survival of keratinocytes, but also contribute to UVB-induced differentiation of keratinocytes. Our results indicate that CPD-dependent signaling acutely maintains skin integrity by supporting cellular energy metabolism.
中波紫外线（UVB）是一种环境完全致癌物，可诱导并促进角质形成细胞癌，这是最常见的人类恶性肿瘤。UVB 会诱导环丁烷嘧啶二聚体（CPD）的形成。在胎盘哺乳动物中，通过核苷酸切除修复来修复 CPD 既缓慢又容易出错。除了致突变和致癌作用外，UVB 还会引发角质形成细胞中尚未完全理解的复杂代谢变化，可能是通过 CPD 引起的。为了确定 CPD 的作用，我们使用含有 N1-甲基假尿嘧啶的体外转录 mRNA 在角质形成细胞中过表达 CPD 光解酶。CPD 光解酶在胎盘哺乳动物中通常不存在，但可以有效地快速修复 CPD，从而阻断 CPD 引发的信号通路。在中波紫外线照射下幸存的角质形成细胞会变得代谢亢进。我们发现，CPD 引发的线粒体活性氧产生，随后激活几种能量传感器酶，包括沉默调节蛋白、AMPK、mTORC1、mTORC2、p53 和 ATM，是角质形成细胞在中波紫外线照射下幸存并进行代偿性代谢适应的原因。代偿性代谢变化包括增强糖酵解通量、 Szent-Györgyi-Krebs 循环和末端氧化。此外，线粒体融合、线粒体生物发生和脂噬表征了暴露于中波紫外线的角质形成细胞中的代偿性代谢亢进。这些特性不仅支持角质形成细胞的存活，而且有助于中波紫外线诱导的角质形成细胞分化。我们的研究结果表明，CPD 依赖性信号通过支持细胞能量代谢来急性维持皮肤完整性。
