TY - JOUR
T1 - Mitochondrial energy metabolism is negatively regulated by cannabinoid receptor 1 in intact human epidermis
AU - Oláh, Attila
AU - Alam, Majid
AU - Chéret, Jérémy
AU - Kis, Nikolett Gréta
AU - Hegyi, Zoltán
AU - Szöllősi, Attila Gábor
AU - Vidali, Silvia
AU - Bíró, Tamás
AU - Paus, Ralf
N1 - Funding Information:
While completed only long thereafter, this project was conceived and initiated when AO, MA, JC and RP worked together in the Dept. of Dermatology, University of M?nster, M?nster, Germany. Therefore, this study is dedicated to Professor Thomas Luger, in gratitude for his generous, unfailing support and in recognition of his inspiring contributions to cutaneous neuroendocrinology. This project was supported in part by an unrestricted basic research grant from Monasterium Laboratory Skin & Hair Research Solutions GmbH, M?nster, Germany, departmental start-up funds from the University of Miami to RP, and by Hungarian (NRDIO 121360, 125055; Hungarian National Brain Research Program [KTIA_NAP_13-1-2013-001]) research grants. AO's work was supported by the J?nos Bolyai Research Scholarship of the Hungarian Academy of Sciences and by the New National Excellence Program (?NKP-19-4-DE-287) of the Ministry for Innovation and Technology of Hungary. The authors are grateful to Dr Marta Bertolini for her expert contribution.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Epidermal energy metabolism is relevant to skin physiology, ageing and photodamage. While selected hormones stimulate epidermal keratinocyte mitochondrial activity, its negative regulation remains unknown. In several cell types, cannabinoid receptor 1 (CB1) is expressed both on the cell membrane (cmCB1) and on the mitochondrial outer membrane (mtCB1), where its stimulation directly suppresses mitochondrial functions. In the current pilot study, we investigated if CB1 is a negative regulator of human epidermal energy metabolism under physiological conditions. Using organ-cultured full-thickness human skin specimens of healthy individuals, we showed that antagonizing the homeostatic CB1 signalling by the administration of the CB1 inverse agonist AM251 increased respiratory chain complex I and II/IV activity. The effect was CB1-dependent, since the CB1-selective agonist arachidonyl-2'-chloroethylamide could prevent the effect. Moreover, the phenomenon was also reproduced by siRNA-mediated down-regulation of CB1. As revealed by the unaltered expression of several relevant markers (TFAM, VDAC1, MTCO1 and NDUFS4), modulation of CB1 signalling had no effect on the epidermal mitochondrial mass. Next, by using immunoelectron microscopy, we found that human epidermal keratinocytes express both cmCB1 and mtCB1. Finally, by using equipotent extracellularly restricted (hemopressin) as well as cell-permeable (AM251) inverse agonists, we found that mitochondrial activity is most likely exclusively regulated by mtCB1. Thus, our data identify mtCB1 as a novel negative regulator of keratinocyte mitochondrial activity in intact human epidermis, and raise the question, whether topical therapeutic interventions capable of selectively activating mtCB1 can reduce excessive mitochondrial ROS production resulting from dysregulated mitochondrial activity during skin ageing or photodamage.
AB - Epidermal energy metabolism is relevant to skin physiology, ageing and photodamage. While selected hormones stimulate epidermal keratinocyte mitochondrial activity, its negative regulation remains unknown. In several cell types, cannabinoid receptor 1 (CB1) is expressed both on the cell membrane (cmCB1) and on the mitochondrial outer membrane (mtCB1), where its stimulation directly suppresses mitochondrial functions. In the current pilot study, we investigated if CB1 is a negative regulator of human epidermal energy metabolism under physiological conditions. Using organ-cultured full-thickness human skin specimens of healthy individuals, we showed that antagonizing the homeostatic CB1 signalling by the administration of the CB1 inverse agonist AM251 increased respiratory chain complex I and II/IV activity. The effect was CB1-dependent, since the CB1-selective agonist arachidonyl-2'-chloroethylamide could prevent the effect. Moreover, the phenomenon was also reproduced by siRNA-mediated down-regulation of CB1. As revealed by the unaltered expression of several relevant markers (TFAM, VDAC1, MTCO1 and NDUFS4), modulation of CB1 signalling had no effect on the epidermal mitochondrial mass. Next, by using immunoelectron microscopy, we found that human epidermal keratinocytes express both cmCB1 and mtCB1. Finally, by using equipotent extracellularly restricted (hemopressin) as well as cell-permeable (AM251) inverse agonists, we found that mitochondrial activity is most likely exclusively regulated by mtCB1. Thus, our data identify mtCB1 as a novel negative regulator of keratinocyte mitochondrial activity in intact human epidermis, and raise the question, whether topical therapeutic interventions capable of selectively activating mtCB1 can reduce excessive mitochondrial ROS production resulting from dysregulated mitochondrial activity during skin ageing or photodamage.
KW - Cannabinoid receptor 1
KW - endocannabinoid
KW - epidermal keratinocyte
KW - mitochondrial activity
KW - mitochondrially expressed cannabinoid receptor 1
UR - http://www.scopus.com/inward/record.url?scp=85085880838&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085880838&partnerID=8YFLogxK
U2 - 10.1111/exd.14110
DO - 10.1111/exd.14110
M3 - Article
C2 - 32367548
AN - SCOPUS:85085880838
VL - 29
SP - 616
EP - 622
JO - Experimental Dermatology
JF - Experimental Dermatology
SN - 0906-6705
IS - 7
ER -