Hypothalamic–Pituitary–Thyroid Axis Hormones Stimulate Mitochondrial Function and Biogenesis in Human Hair Follicles

Abstract

Thyroid hormones regulate mitochondrial function. As other hypothalamic-pituitary-thyroid (HPT) axis hormones, i.e., thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), are expressed in human hair follicles (HFs) and regulate mitochondrial function in human epidermis, we investigated in organ-cultured human scalp HFs whether TRH (30 nM), TSH (10 mU ml(-1)), thyroxine (T4) (100 nM), and triiodothyronine (T3) (100 pM) alter intrafollicular mitochondrial energy metabolism. All HPT-axis members increased gene and protein expression of mitochondrial-encoded subunit 1 of cytochrome c oxidase (MTCO1), a subunit of respiratory chain complex IV, mitochondrial transcription factor A (TFAM), and Porin. All hormones also stimulated intrafollicular complex I/IV activity and mitochondrial biogenesis. The TSH effects on MTCO1, TFAM, and porin could be abolished by K1-70, a TSH-receptor antagonist, suggesting a TSH receptor-mediated action. Notably, as measured by calorimetry, T3 and TSH increased follicular heat production, whereas T3/T4 and TRH stimulated ATP production in cultured HF keratinocytes. HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable.

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

“…The mitochondrial data here presented suggest that THs stimulate intraepidermal mitochondrial biogenesis (Supplementary Figure S3) as they do in many other tissues, including human hair follicles (Cioffi et al, 2013;Lee et al, 2012;Marin-Garcia, 2010;Santillo et al, 2013;Vakitus et al, 2015;Vidali et al, 2014), via a sirt1-PGC1α-mediated pathway. Also, both THs decreased mTORC1/2, whose inhibition is involved in mitochondrial biogenesis and reportedly restores a more juvenile phenotype and increased life span (Chiao et al, 2016;Evangelisti et al, 2016;Johnson et al, 2013).…”

“…As the latter is difficult to assess in tissue sections, this was examined in cultured primary human epidermal keratinocytes (NHEK), using a ROS-specific dye (CM-H2DCFDA) (Vidali et al, 2014). This showed that treatment with different concentrations of either T 3 (50, 100 and 200 pM) or T 4 (50, 100 and 200 nM) for 24 hours failed to increase ROS production (Supplementary Figure S6).…”

“…After a 24 hour pre-incubation period, vehicle (William' s E Medium), T 3 (100 pM), T 4 (100 nM) (Sigma-Aldrich; Steinheim, Germany) were added to the media for 24 hours or 6 days. For the 6 days incubation, medium and treatments were changed every second day; TH concentrations were selected based on their documented stimulatory effects on human hair growth (van Beek et al, 2008) and mitochondrial function within human hair follicle epithelium (Vidali et al, 2014). Human skin largely remains morphologically intact and shows continued proliferative activity under these long-term organ culture conditions (Lu et al, 2007).…”

“…To assess whether any expression changes in these parameters altered also the intraepidermal mitochondrial oxidative phosphorylation, we asked whether THs modified the activity of complex I, the initial step of the mitochondrial respiratory chain (Chandel and Jeffs, 2015;Hirst, 2013;Scheffler, 2008). Finally, since THs stimulate mitochondrial biogenesis in several human cell types ( Cioffi et al, 2013;Lee et al, 2012;Marin-Garcia, 2010) and human hair follicles (Vidali et al, 2014), we asked by transmission electron microscopy whether this also occurred in human epidermis ex vivo.…”

Thermogenesis and longevity in mammals. Thyroxin model of accelerated aging

“…Thyroxin has a strong polyfunctional action: it increases basal metabolism (Alva-Sánchez et al, 2012), activates mitochondrial function (Vidali et al, 2014), changes water and mineral metabolism (Reddy On the axes: 1 -mitochondrial respiratory control; 2 -content of TBARS in microsomal fractions; 3 -the rate of generation of superoxide radical in microsomal fractions; 4 -content of TBARS in the mitochondrial fraction; 5 -malate dehydrogenase activity; 6 -the rate of generation of free radicals in the mitochondrial fraction; 7 -rate of oxygen consumption in state V2; 8 -rate of oxygen consumption in state V3; 9 -glutathione reductase activity; 10 -glutathione peroxidase activity; 11 -activity of isocitrate dehydrogenase; 12 -activity of glutathione-S-transferase. et al, 2012), increases mitochondrial membrane permeability (Maity et al, 2013), and activates transcription of several genes (Yap et al, 2013) and can regulate other cell functions.…”