PUBLICATION
NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism
- Authors
- Allouche, J., Rachmin, I., Adhikari, K., Pardo, L.M., Lee, J.H., McConnell, A.M., Kato, S., Fan, S., Kawakami, A., Suita, Y., Wakamatsu, K., Igras, V., Zhang, J., Navarro, P.P., Lugo, C.M., Noonan, H.R., Christie, K.A., Itin, K., Mujahid, N., Lo, J.A., Won, C.H., Evans, C.L., Weng, Q.Y., Wang, H., Osseiran, S., Lovas, A., Németh, I., Cozzio, A., Navarini, A.A., Hsiao, J.J., Nguyen, N., Kemény, L.V., Iliopoulos, O., Berking, C., Ruzicka, T., Gonzalez-José, R., Bortolini, M.C., Canizales-Quinteros, S., Acuna-Alonso, V., Gallo, C., Poletti, G., Bedoya, G., Rothhammer, F., Ito, S., Schiaffino, M.V., Chao, L.H., Kleinstiver, B.P., Tishkoff, S., Zon, L.I., Nijsten, T., Ruiz-Linares, A., Fisher, D.E., Roider, E.
- ID
- ZDB-PUB-210708-8
- Date
- 2021
- Source
- Cell 184(16): 4268-4283.e20 (Journal)
- Registered Authors
- Keywords
- MITF, UVB, melanosome, nicotinamide nucleotide transhydrogenase, pigmentation, redox regulation
- MeSH Terms
-
- Cyclic AMP/metabolism
- Microphthalmia-Associated Transcription Factor/metabolism*
- Melanosomes/drug effects
- Melanosomes/metabolism
- Melanosomes/radiation effects
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacology
- NADP Transhydrogenases/antagonists & inhibitors
- NADP Transhydrogenases/metabolism*
- Ultraviolet Rays*
- Mitochondria/drug effects
- Mitochondria/metabolism
- DNA Damage
- Cohort Studies
- Humans
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Monophenol Monooxygenase/genetics
- Monophenol Monooxygenase/metabolism
- Zebrafish
- Proteolysis/drug effects
- Proteolysis/radiation effects
- Oxidation-Reduction/drug effects
- Oxidation-Reduction/radiation effects
- Ubiquitin/metabolism
- Skin Pigmentation/drug effects
- Skin Pigmentation/genetics
- Skin Pigmentation/radiation effects*
- Genetic Predisposition to Disease
- Cell Line
- Mice, Inbred C57BL
- Animals
- Polymorphism, Single Nucleotide/genetics
- Melanocytes/drug effects
- Melanocytes/metabolism
- Mice
- Proteasome Endopeptidase Complex/metabolism
- PubMed
- 34233163 Full text @ Cell
Citation
Allouche, J., Rachmin, I., Adhikari, K., Pardo, L.M., Lee, J.H., McConnell, A.M., Kato, S., Fan, S., Kawakami, A., Suita, Y., Wakamatsu, K., Igras, V., Zhang, J., Navarro, P.P., Lugo, C.M., Noonan, H.R., Christie, K.A., Itin, K., Mujahid, N., Lo, J.A., Won, C.H., Evans, C.L., Weng, Q.Y., Wang, H., Osseiran, S., Lovas, A., Németh, I., Cozzio, A., Navarini, A.A., Hsiao, J.J., Nguyen, N., Kemény, L.V., Iliopoulos, O., Berking, C., Ruzicka, T., Gonzalez-José, R., Bortolini, M.C., Canizales-Quinteros, S., Acuna-Alonso, V., Gallo, C., Poletti, G., Bedoya, G., Rothhammer, F., Ito, S., Schiaffino, M.V., Chao, L.H., Kleinstiver, B.P., Tishkoff, S., Zon, L.I., Nijsten, T., Ruiz-Linares, A., Fisher, D.E., Roider, E. (2021) NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell. 184(16):4268-4283.e20.
Abstract
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping