NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

Jennifer Allouche; Inbal Rachmin; Kaustubh Adhikari; Luba M. Pardo; Ju Hee Lee; Alicia M. McConnell; Shinichiro Kato; Shaohua Fan; Akinori Kawakami; Yusuke Suita; Kazumasa Wakamatsu; Vivien Igras; Jianming Zhang; Paula P. Navarro; Camila Makhlouta Lugo; Haley R. Noonan; Kathleen A. Christie; Kaspar Itin; Nisma Mujahid; Jennifer A. Lo; Chong Hyun Won; Conor L. Evans; Qing Yu Weng; Hequn Wang; Sam Osseiran; Alyssa Lovas; István Németh; Antonio Cozzio; Alexander A. Navarini; Jennifer J. Hsiao; Nhu Nguyen; Lajos V. Kemény; Othon Iliopoulos; Carola Berking; Thomas Ruzicka; Rolando Gonzalez-José; Maria Cátira Bortolini; Samuel Canizales-Quinteros; Victor Acuna-Alonso; Carla Gallo; Giovanni Poletti; Gabriel Bedoya; Francisco Rothhammer; Shosuke Ito; Maria Vittoria Schiaffino; Luke H. Chao; Benjamin P. Kleinstiver; Sarah Tishkoff; Leonard I. Zon; Tamar Nijsten; Andrés Ruiz-Linares; David E. Fisher; Elisabeth Roider

doi:10.1016/j.cell.2021.06.022

NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

Jennifer Allouche
, Inbal Rachmin
, Kaustubh Adhikari
, Luba M. Pardo
, Ju Hee Lee
, Alicia M. McConnell
, Shinichiro Kato
, Shaohua Fan
, Akinori Kawakami
, Yusuke Suita
, Kazumasa Wakamatsu
, Vivien Igras
, Jianming Zhang
, Paula P. Navarro
, Camila Makhlouta Lugo
, Haley R. Noonan
, Kathleen A. Christie
, Kaspar Itin
, Nisma Mujahid
, Jennifer A. Lo

Chong Hyun Won, Conor L. Evans, Qing Yu Weng, Hequn Wang, Sam Osseiran, Alyssa Lovas, István Németh, Antonio Cozzio, Alexander A. Navarini, Jennifer J. Hsiao, Nhu Nguyen, Lajos V. Kemény, Othon Iliopoulos, Carola Berking, Thomas Ruzicka, Rolando Gonzalez-José, Maria Cátira Bortolini, Samuel Canizales-Quinteros, Victor Acuna-Alonso, Carla Gallo, Giovanni Poletti, Gabriel Bedoya, Francisco Rothhammer, Shosuke Ito, Maria Vittoria Schiaffino, Luke H. Chao, Benjamin P. Kleinstiver, Sarah Tishkoff, Leonard I. Zon, Tamar Nijsten, Andrés Ruiz-Linares, David E. Fisher, Elisabeth Roider

Instituto de Alta Investigación

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

64 Citas (Scopus)

Resumen

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.

Idioma original	Inglés
Páginas (desde-hasta)	4268-4283.e20
Publicación	Cell
Volumen	184
N.º	16
DOI	https://doi.org/10.1016/j.cell.2021.06.022
Estado	Publicada - 5 ago. 2021

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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., ... Roider, E. (2021). NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell, 184(16), 4268-4283.e20. https://doi.org/10.1016/j.cell.2021.06.022

@article{5c4d4a6a37f348c78406c8bd471451bd,

title = "NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism",

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.",

keywords = "MITF, UVB, melanosome, nicotinamide nucleotide transhydrogenase, pigmentation, redox regulation",

author = "Jennifer Allouche and Inbal Rachmin and Kaustubh Adhikari and Pardo, \{Luba M.\} and Lee, \{Ju Hee\} and McConnell, \{Alicia M.\} and Shinichiro Kato and Shaohua Fan and Akinori Kawakami and Yusuke Suita and Kazumasa Wakamatsu and Vivien Igras and Jianming Zhang and Navarro, \{Paula P.\} and Lugo, \{Camila Makhlouta\} and Noonan, \{Haley R.\} and Christie, \{Kathleen A.\} and Kaspar Itin and Nisma Mujahid and Lo, \{Jennifer A.\} and Won, \{Chong Hyun\} and Evans, \{Conor L.\} and Weng, \{Qing Yu\} and Hequn Wang and Sam Osseiran and Alyssa Lovas and Istv{\'a}n N{\'e}meth and Antonio Cozzio and Navarini, \{Alexander A.\} and Hsiao, \{Jennifer J.\} and Nhu Nguyen and Kem{\'e}ny, \{Lajos V.\} and Othon Iliopoulos and Carola Berking and Thomas Ruzicka and Rolando Gonzalez-Jos{\'e} and Bortolini, \{Maria C{\'a}tira\} and Samuel Canizales-Quinteros and Victor Acuna-Alonso and Carla Gallo and Giovanni Poletti and Gabriel Bedoya and Francisco Rothhammer and Shosuke Ito and Schiaffino, \{Maria Vittoria\} and Chao, \{Luke H.\} and Kleinstiver, \{Benjamin P.\} and Sarah Tishkoff and Zon, \{Leonard I.\} and Tamar Nijsten and Andr{\'e}s Ruiz-Linares and Fisher, \{David E.\} and Elisabeth Roider",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = aug,

day = "5",

doi = "10.1016/j.cell.2021.06.022",

language = "English",

volume = "184",

pages = "4268--4283.e20",

journal = "Cell",

issn = "0092-8674",

number = "16",

}

Allouche, J, Rachmin, I, Adhikari, K, Pardo, LM, Lee, JH, McConnell, AM, Kato, S, Fan, S, Kawakami, A, Suita, Y, Wakamatsu, K, Igras, V, Zhang, J, Navarro, PP, Lugo, CM, Noonan, HR, Christie, KA, Itin, K, Mujahid, N, Lo, JA, Won, CH, Evans, CL, Weng, QY, Wang, H, Osseiran, S, Lovas, A, Németh, I, Cozzio, A, Navarini, AA, Hsiao, JJ, Nguyen, N, Kemény, LV, Iliopoulos, O, Berking, C, Ruzicka, T, Gonzalez-José, R, Bortolini, MC, Canizales-Quinteros, S, Acuna-Alonso, V, Gallo, C, Poletti, G, Bedoya, G, Rothhammer, F, Ito, S, Schiaffino, MV, Chao, LH, Kleinstiver, BP, Tishkoff, S, Zon, LI, Nijsten, T, Ruiz-Linares, A, Fisher, DE & Roider, E 2021, 'NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism', Cell, vol. 184, n.º 16, pp. 4268-4283.e20. https://doi.org/10.1016/j.cell.2021.06.022

TY - JOUR

T1 - NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

AU - Allouche, Jennifer

AU - Rachmin, Inbal

AU - Adhikari, Kaustubh

AU - Pardo, Luba M.

AU - Lee, Ju Hee

AU - McConnell, Alicia M.

AU - Kato, Shinichiro

AU - Fan, Shaohua

AU - Kawakami, Akinori

AU - Suita, Yusuke

AU - Wakamatsu, Kazumasa

AU - Igras, Vivien

AU - Zhang, Jianming

AU - Navarro, Paula P.

AU - Lugo, Camila Makhlouta

AU - Noonan, Haley R.

AU - Christie, Kathleen A.

AU - Itin, Kaspar

AU - Mujahid, Nisma

AU - Lo, Jennifer A.

AU - Won, Chong Hyun

AU - Evans, Conor L.

AU - Weng, Qing Yu

AU - Wang, Hequn

AU - Osseiran, Sam

AU - Lovas, Alyssa

AU - Németh, István

AU - Cozzio, Antonio

AU - Navarini, Alexander A.

AU - Hsiao, Jennifer J.

AU - Nguyen, Nhu

AU - Kemény, Lajos V.

AU - Iliopoulos, Othon

AU - Berking, Carola

AU - Ruzicka, Thomas

AU - Gonzalez-José, Rolando

AU - Bortolini, Maria Cátira

AU - Canizales-Quinteros, Samuel

AU - Acuna-Alonso, Victor

AU - Gallo, Carla

AU - Poletti, Giovanni

AU - Bedoya, Gabriel

AU - Rothhammer, Francisco

AU - Ito, Shosuke

AU - Schiaffino, Maria Vittoria

AU - Chao, Luke H.

AU - Kleinstiver, Benjamin P.

AU - Tishkoff, Sarah

AU - Zon, Leonard I.

AU - Nijsten, Tamar

AU - Ruiz-Linares, Andrés

AU - Fisher, David E.

AU - Roider, Elisabeth

PY - 2021/8/5

Y1 - 2021/8/5

N2 - 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.

AB - 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.

KW - MITF

KW - UVB

KW - melanosome

KW - nicotinamide nucleotide transhydrogenase

KW - pigmentation

KW - redox regulation

UR - https://www.scopus.com/pages/publications/85111783140

U2 - 10.1016/j.cell.2021.06.022

DO - 10.1016/j.cell.2021.06.022

M3 - Article

C2 - 34233163

AN - SCOPUS:85111783140

SN - 0092-8674

VL - 184

SP - 4268-4283.e20

JO - Cell

JF - Cell

IS - 16

ER -

NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

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