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
-
- Ultraviolet Rays*
- Zebrafish
- Melanosomes/drug effects
- Melanosomes/metabolism
- Melanosomes/radiation effects
- Proteolysis/drug effects
- Proteolysis/radiation effects
- Oxidation-Reduction/drug effects
- Oxidation-Reduction/radiation effects
- Mice
- Ubiquitin/metabolism
- Humans
- Genetic Predisposition to Disease
- Mice, Inbred C57BL
- Mitochondria/drug effects
- Mitochondria/metabolism
- Microphthalmia-Associated Transcription Factor/metabolism*
- Animals
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacology
- Proteasome Endopeptidase Complex/metabolism
- NADP Transhydrogenases/antagonists & inhibitors
- NADP Transhydrogenases/metabolism*
- DNA Damage
- Polymorphism, Single Nucleotide/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Skin Pigmentation/drug effects
- Skin Pigmentation/genetics
- Skin Pigmentation/radiation effects*
- Cyclic AMP/metabolism
- Melanocytes/drug effects
- Melanocytes/metabolism
- Cell Line
- Monophenol Monooxygenase/genetics
- Monophenol Monooxygenase/metabolism
- Cohort Studies
- 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