Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

• Published in: Journal of investigative dermatology Vol. 136; no. 10; pp. 2003 - 2012
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2016
• Subjects: Administration, Cutaneous; Cells, Cultured; Down-Regulation - drug effects; Epidermis - drug effects; Epidermis - metabolism; Humans; Keratinocytes - drug effects; Keratinocytes - metabolism; Matrix Metalloproteinases - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Organ Culture Techniques; Reactive Oxygen Species - metabolism; Skin Aging - physiology; Skin Diseases - drug therapy; Skin Diseases - pathology; Thyroxine - administration & dosage; Thyroxine - pharmacology; Triiodothyronine - administration & dosage; Triiodothyronine - pharmacology; T4; NBT; PGC1α; mTORC1/2; IR; MMP; TH; ROS; P16ink4; TFAM; MTCO1; ATP; sirt1; T3
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2016.05.118

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 (p16ink4) 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.