Vidali Silvia, Chéret Jérémy, Giesen Melanie, Haeger Swantje, Alam Majid, Watson Rachel E B, Langton Abigail K, Klinger Matthias, Knuever Jana, Funk Wolfgang, Kofler Barbara, Paus Ralf
Department of Dermatology, University of Luebeck, Luebeck, Germany; Research Program for Receptor Biochemistry and Tumor Metabolism, Laura Bassi Centre of Expertise-THERAPEP, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
Department of Dermatology, University of Münster, Münster, Germany.
J Invest Dermatol. 2016 Oct;136(10):2003-2012. doi: 10.1016/j.jid.2016.05.118. Epub 2016 Jun 25.
Since it is unknown whether thyroid hormones (THs) regulate mitochondrial function in human epidermis, we treated organ-cultured human skin, or isolated cultured human epidermal keratinocytes, with triiodothyronine (100 pmol/L) or thyroxine (100 nmol/L). Both THs significantly increased protein expression of the mitochondrially encoded cytochrome C oxidase I (MTCO1), complex I activity, and the number of perinuclear mitochondria. Triiodothyronine also increased mitochondrial transcription factor A (TFAM) protein expression, and thyroxine stimulated complex II/IV activity. Increased mitochondrial function can correlate with increased reactive oxygen species production, DNA damage, and accelerated tissue aging. However, THs neither raised reactive oxygen species production or matrix metalloproteinase-1, -2 and -9 activity nor decreased sirtuin1 (Sirt1) immunoreactivity. Instead, triiodothyronine increased sirtuin-1, fibrillin-1, proliferator-activated receptor-gamma 1-alpha (PGC1α), collagen I and III transcription, and thyroxine decreased cyclin-dependent kinase inhibitor 2A (p16(ink4)) expression in organ-cultured human skin. Moreover, TH treatment increased intracutaneous fibrillin-rich microfibril and collagen III deposition and decreased mammalian target of rapamycin (mTORC1/2) expression ex vivo. This identifies THs as potent endocrine stimulators of mitochondrial function in human epidermis, which down-regulates rather than enhance the expression of skin aging-related biomarkers ex vivo. Therefore, topically applied THs deserve further exploration as candidate agents for treating skin conditions characterized by reduced mitochondrial function.
由于甲状腺激素（THs）是否调节人类表皮中的线粒体功能尚不清楚，我们用三碘甲状腺原氨酸（100 pmol/L）或甲状腺素（100 nmol/L）处理器官培养的人类皮肤或分离培养的人类表皮角质形成细胞。两种甲状腺激素均显著增加线粒体编码的细胞色素C氧化酶I（MTCO1）的蛋白表达、复合体I活性以及核周线粒体的数量。三碘甲状腺原氨酸还增加线粒体转录因子A（TFAM）的蛋白表达，而甲状腺素刺激复合体II/IV活性。线粒体功能增强可能与活性氧生成增加、DNA损伤及组织衰老加速相关。然而，甲状腺激素既未提高活性氧生成或基质金属蛋白酶-1、-2和-9的活性，也未降低沉默调节蛋白1（Sirt1）的免疫反应性。相反，在器官培养的人类皮肤中，三碘甲状腺原氨酸增加沉默调节蛋白-1、原纤蛋白-1、增殖激活受体-γ1-α（PGC1α）、胶原蛋白I和III的转录，而甲状腺素降低细胞周期蛋白依赖性激酶抑制剂2A（p16(ink4)）的表达。此外，甲状腺激素处理在体外增加了富含原纤蛋白的微原纤维和胶原蛋白III在皮内的沉积，并降低了雷帕霉素靶蛋白（mTORC1/2）的表达。这表明甲状腺激素是人类表皮中线粒体功能的强效内分泌刺激物，在体外可下调而非增强皮肤衰老相关生物标志物的表达。因此，局部应用甲状腺激素作为治疗以线粒体功能降低为特征的皮肤疾病的候选药物值得进一步探索。
