Mitochondrial energy metabolism is negatively regulated by cannabinoid receptor 1 in intact human epidermis:
Abstract
Epidermal energy metabolism is relevant to skin physiology, aging, and photodamage. While selected hormones stimulate epidermal keratinocyte mitochondrial activity, its negative regulation remains unknown. In several cell types, cannabinoid receptor 1 (CB
1) is expressed both in the cell membrane (cmCB
1), and in the mitochondrial outer membrane (mtCB
1), where its stimulation directly suppresses mitochondrial functions. In the current pilot study, we investigated if CB
1 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 CB
1 signaling by the administration of the CB
1 inverse agonist AM251 increased activity of respiratory chain complex I and II/IV activity in a CB
1‐dependent manner, since the CB
1‐selective agonist arachidonyl‐2'‐chloroethylamide could prevent the effect. Moreover, the phenomenon was also reproduced by siRNA‐mediated down‐regulation of CB
1. As revealed by the unaltered expression of several relevant markers (TFAM, VDAC1, MTCO1, and NDUFS4), modulation of CB
1 signaling had no effect on the epidermal mitochondrial mass. Next, by using immunoelectron microscopy, we found that human epidermal keratinocytes express both cmCB
1 and mtCB
1. 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 mtCB
1. Thus, our data identify mtCB
1 as a negative regulator of keratinocyte mitochondrial activity in intact human epidermis, and highlight the question, whether topical therapeutic interventions capable of selectively activating mtCB
1 can reduce excessive mitochondrial ROS production resulting from dysregulated mitochondrial activity during skin aging or photodamage.
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