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. LoChong 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

Department of Dermatology

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

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.

Original language	English
Pages (from-to)	4268-4283.e20
Journal	Cell
Volume	184
Issue number	16
DOIs	https://doi.org/10.1016/j.cell.2021.06.022
Publication status	Published - 2021 Aug 5

Bibliographical note

Funding Information:
We thank C. Thomas Powell and Robert Liu for help with statistical analysis and editing, Diane Capen for help with electron microscopy-related questions, Sharon Germana for administrative help, Paolo Gameiro for providing plasmid constructs, Pawel Pelczar for his efforts to generate transgenic mice, and Ruth Halaban, Micky Marks, Doug Richardson, Desmond Tobin, Rizwan Haq, Pere Puigserver, Alfred Goldberg, Lajos Kemeny senior, and Steven Gygi for helpful discussions. E.R. gratefully acknowledges support from the Mildred Scheel Grant of the German Cancer Society and the Filling the Gap Grant of the University of Zurich , Switzerland. D.E.F. gratefully acknowledges support from NIH grants 5P01-CA163222 , 5R01CA222871 , 5R01AR043369 , and 5R01AR072304 and the Dr. Miriam and Sheldon Adelson Medical Research Foundation . S.T. is funded by NIH grants R01AR076241 and R35 GM134957-01 . This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center ( National Center for Advancing Translational Sciences , National Institutes of Health award UL 1TR002541 ) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. P.P.N. was supported by the Swiss National Science Foundation (SNSF). Early Postdoctoral Mobility Fellowship CRSII3_154461 and Postdoctoral Mobility Fellowship P400PB_199252 . B.P.K. was supported by NCI R00 CA218870 and NHLBI P01 HL142494 . K.A. was supported by the Santander Research and Scholarship Award, and Bogue Fellowship from University College London . A.R.L. was supported by the Leverhulme Trust ( F/07 134/DF ), BBSRC ( BB/I021213/1 ), the Excellence Initiative of Aix-Marseille University - A ∗ MIDEX (a French “Investissements d’Avenir” program, 2RUIZLRE/RHRE/ID18HRU201 and 20-07874 ), the National Natural Science Foundation of China ( 31771393 ), the Scientific and Technology Committee of Shanghai Municipality ( 18490750300 ), the Ministry of Science and Technology of China ( 2020YFE0201600 ), the Shanghai Municipal Science and Technology Major Project ( 2017SHZDZX01 ), and the 111 Project ( B13016 ). G.B. was supported by the Universidad de Antioquia ( CODI sostenibilidad de grupos 2013–2014 and MASO 2013–2014 ). L.V.K. is a recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam (the Netherlands); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly ; the Ministry of Education, Culture and Science ; the Ministry for Health, Welfare and Sports ; the European Commission (DG XII); and the Municipality of Rotterdam . The Microscopy Core of the MGH Program in Membrane Biology is partially supported by Inflammatory Bowel Disease Center grant DK043351 and Boston Area Diabetes Endocrinology Research Center grant DK057521 .

Funding Information:
We thank C. Thomas Powell and Robert Liu for help with statistical analysis and editing, Diane Capen for help with electron microscopy-related questions, Sharon Germana for administrative help, Paolo Gameiro for providing plasmid constructs, Pawel Pelczar for his efforts to generate transgenic mice, and Ruth Halaban, Micky Marks, Doug Richardson, Desmond Tobin, Rizwan Haq, Pere Puigserver, Alfred Goldberg, Lajos Kemeny senior, and Steven Gygi for helpful discussions. E.R. gratefully acknowledges support from the Mildred Scheel Grant of the German Cancer Society and the Filling the Gap Grant of the University of Zurich, Switzerland. D.E.F. gratefully acknowledges support from NIH grants 5P01-CA163222, 5R01CA222871, 5R01AR043369, and 5R01AR072304 and the Dr. Miriam and Sheldon Adelson Medical Research Foundation. S.T. is funded by NIH grants R01AR076241 and R35 GM134957-01. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. P.P.N. was supported by the Swiss National Science Foundation (SNSF). Early Postdoctoral Mobility Fellowship CRSII3_154461 and Postdoctoral Mobility Fellowship P400PB_199252. B.P.K. was supported by NCI R00 CA218870 and NHLBI P01 HL142494. K.A. was supported by the Santander Research and Scholarship Award, and Bogue Fellowship from University College London. A.R.L. was supported by the Leverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative of Aix-Marseille University - A∗MIDEX (a French “Investissements d'Avenir” program, 2RUIZLRE/RHRE/ID18HRU201 and 20-07874), the National Natural Science Foundation of China (31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), the Ministry of Science and Technology of China (2020YFE0201600), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the 111 Project (B13016). G.B. was supported by the Universidad de Antioquia (CODI sostenibilidad de grupos 2013–2014 and MASO 2013–2014). L.V.K. is a recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam (the Netherlands); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The Microscopy Core of the MGH Program in Membrane Biology is partially supported by Inflammatory Bowel Disease Center grant DK043351 and Boston Area Diabetes Endocrinology Research Center grant DK057521. E.R. and D.E.F. conceived the project. E.R. J.A. I.R. and D.E.F. designed and discussed the experiments. E.R. I.R. J.A. Y.S. S.K. A.K. V.I. J.Z. H.W. A.L. M.V.S. K.W. B.P.K. K.A.C. and S.I. performed in vitro studies. J.A. I.R. and J.H.L. performed histological analyses. A.C. H.R.N. and L.Z. performed zebrafish experiments. E.R. V.I. J.A. and J.A.L. performed mouse studies and prepared photographic images. K.A. L.M.P. S.F. R.G.-J. M.-C.B. S.C.-Q. V.A.-A. C.G. G.P. G.B. F.R. T.N. S.T. and A.R.-L. performed human genetic association studies. C.M.L. N.M. J.A.L. C.H.W. S.O. J.Z. N.N. Q.Y.W. H.W. C.L.E. M.V.S. P.P.N. K.I. I.N. L.H.C. A.A.N. J.J.H. C.B. and T.R. assisted with the experimental design and data interpretation. E.R. J.A. I.R,. K.A. L.M.P. and S.K. prepared figures. E.R. I.R. K.A. J.A. and D.E.F. wrote the manuscript. All authors discussed the results and commented on the manuscript. D.E.F. and E.R. have a patent filed on “Methods and compositions for enhancing skin pigmentation” (publication number WO/2016/077817, May 19, 2016.). D.E.F. has a financial interest in Soltego, Inc. a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. D.E.F.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. B.P.K. is an inventor on patents and patent applications filed by Mass General Brigham that describe genome engineering technologies. B.P.K. consults for Avectas Inc. ElevateBio, and EcoR1 capital and is an advisor to Acrigen Biosciences. Q.Y.W. is a shareholder in Mymiel Skincare. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, and Scholar Rock. He is a consultant for Celularity and Cellarity. H.W. is an employee and shareholder of Johnson and Johnson.

Publisher Copyright:
© 2021 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.cell.2021.06.022

Cite this

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{e4b19edaee3c42249b1e7b154e1a6daf,

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.",

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 = "Funding Information: We thank C. Thomas Powell and Robert Liu for help with statistical analysis and editing, Diane Capen for help with electron microscopy-related questions, Sharon Germana for administrative help, Paolo Gameiro for providing plasmid constructs, Pawel Pelczar for his efforts to generate transgenic mice, and Ruth Halaban, Micky Marks, Doug Richardson, Desmond Tobin, Rizwan Haq, Pere Puigserver, Alfred Goldberg, Lajos Kemeny senior, and Steven Gygi for helpful discussions. E.R. gratefully acknowledges support from the Mildred Scheel Grant of the German Cancer Society and the Filling the Gap Grant of the University of Zurich , Switzerland. D.E.F. gratefully acknowledges support from NIH grants 5P01-CA163222 , 5R01CA222871 , 5R01AR043369 , and 5R01AR072304 and the Dr. Miriam and Sheldon Adelson Medical Research Foundation . S.T. is funded by NIH grants R01AR076241 and R35 GM134957-01 . This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center ( National Center for Advancing Translational Sciences , National Institutes of Health award UL 1TR002541 ) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. P.P.N. was supported by the Swiss National Science Foundation (SNSF). Early Postdoctoral Mobility Fellowship CRSII3_154461 and Postdoctoral Mobility Fellowship P400PB_199252 . B.P.K. was supported by NCI R00 CA218870 and NHLBI P01 HL142494 . K.A. was supported by the Santander Research and Scholarship Award, and Bogue Fellowship from University College London . A.R.L. was supported by the Leverhulme Trust ( F/07 134/DF ), BBSRC ( BB/I021213/1 ), the Excellence Initiative of Aix-Marseille University - A ∗ MIDEX (a French “Investissements d{\textquoteright}Avenir” program, 2RUIZLRE/RHRE/ID18HRU201 and 20-07874 ), the National Natural Science Foundation of China ( 31771393 ), the Scientific and Technology Committee of Shanghai Municipality ( 18490750300 ), the Ministry of Science and Technology of China ( 2020YFE0201600 ), the Shanghai Municipal Science and Technology Major Project ( 2017SHZDZX01 ), and the 111 Project ( B13016 ). G.B. was supported by the Universidad de Antioquia ( CODI sostenibilidad de grupos 2013–2014 and MASO 2013–2014 ). L.V.K. is a recipient of the J{\'a}nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam (the Netherlands); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly ; the Ministry of Education, Culture and Science ; the Ministry for Health, Welfare and Sports ; the European Commission (DG XII); and the Municipality of Rotterdam . The Microscopy Core of the MGH Program in Membrane Biology is partially supported by Inflammatory Bowel Disease Center grant DK043351 and Boston Area Diabetes Endocrinology Research Center grant DK057521 . Funding Information: We thank C. Thomas Powell and Robert Liu for help with statistical analysis and editing, Diane Capen for help with electron microscopy-related questions, Sharon Germana for administrative help, Paolo Gameiro for providing plasmid constructs, Pawel Pelczar for his efforts to generate transgenic mice, and Ruth Halaban, Micky Marks, Doug Richardson, Desmond Tobin, Rizwan Haq, Pere Puigserver, Alfred Goldberg, Lajos Kemeny senior, and Steven Gygi for helpful discussions. E.R. gratefully acknowledges support from the Mildred Scheel Grant of the German Cancer Society and the Filling the Gap Grant of the University of Zurich, Switzerland. D.E.F. gratefully acknowledges support from NIH grants 5P01-CA163222, 5R01CA222871, 5R01AR043369, and 5R01AR072304 and the Dr. Miriam and Sheldon Adelson Medical Research Foundation. S.T. is funded by NIH grants R01AR076241 and R35 GM134957-01. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. P.P.N. was supported by the Swiss National Science Foundation (SNSF). Early Postdoctoral Mobility Fellowship CRSII3_154461 and Postdoctoral Mobility Fellowship P400PB_199252. B.P.K. was supported by NCI R00 CA218870 and NHLBI P01 HL142494. K.A. was supported by the Santander Research and Scholarship Award, and Bogue Fellowship from University College London. A.R.L. was supported by the Leverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative of Aix-Marseille University - A∗MIDEX (a French “Investissements d'Avenir” program, 2RUIZLRE/RHRE/ID18HRU201 and 20-07874), the National Natural Science Foundation of China (31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), the Ministry of Science and Technology of China (2020YFE0201600), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the 111 Project (B13016). G.B. was supported by the Universidad de Antioquia (CODI sostenibilidad de grupos 2013–2014 and MASO 2013–2014). L.V.K. is a recipient of the J{\'a}nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam (the Netherlands); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The Microscopy Core of the MGH Program in Membrane Biology is partially supported by Inflammatory Bowel Disease Center grant DK043351 and Boston Area Diabetes Endocrinology Research Center grant DK057521. E.R. and D.E.F. conceived the project. E.R. J.A. I.R. and D.E.F. designed and discussed the experiments. E.R. I.R. J.A. Y.S. S.K. A.K. V.I. J.Z. H.W. A.L. M.V.S. K.W. B.P.K. K.A.C. and S.I. performed in vitro studies. J.A. I.R. and J.H.L. performed histological analyses. A.C. H.R.N. and L.Z. performed zebrafish experiments. E.R. V.I. J.A. and J.A.L. performed mouse studies and prepared photographic images. K.A. L.M.P. S.F. R.G.-J. M.-C.B. S.C.-Q. V.A.-A. C.G. G.P. G.B. F.R. T.N. S.T. and A.R.-L. performed human genetic association studies. C.M.L. N.M. J.A.L. C.H.W. S.O. J.Z. N.N. Q.Y.W. H.W. C.L.E. M.V.S. P.P.N. K.I. I.N. L.H.C. A.A.N. J.J.H. C.B. and T.R. assisted with the experimental design and data interpretation. E.R. J.A. I.R,. K.A. L.M.P. and S.K. prepared figures. E.R. I.R. K.A. J.A. and D.E.F. wrote the manuscript. All authors discussed the results and commented on the manuscript. D.E.F. and E.R. have a patent filed on “Methods and compositions for enhancing skin pigmentation” (publication number WO/2016/077817, May 19, 2016.). D.E.F. has a financial interest in Soltego, Inc. a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. D.E.F.{\textquoteright}s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. B.P.K. is an inventor on patents and patent applications filed by Mass General Brigham that describe genome engineering technologies. B.P.K. consults for Avectas Inc. ElevateBio, and EcoR1 capital and is an advisor to Acrigen Biosciences. Q.Y.W. is a shareholder in Mymiel Skincare. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, and Scholar Rock. He is a consultant for Celularity and Cellarity. H.W. is an employee and shareholder of Johnson and Johnson. 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",

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publisher = "Cell Press",

number = "16",

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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, no. 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

N1 - Funding Information: We thank C. Thomas Powell and Robert Liu for help with statistical analysis and editing, Diane Capen for help with electron microscopy-related questions, Sharon Germana for administrative help, Paolo Gameiro for providing plasmid constructs, Pawel Pelczar for his efforts to generate transgenic mice, and Ruth Halaban, Micky Marks, Doug Richardson, Desmond Tobin, Rizwan Haq, Pere Puigserver, Alfred Goldberg, Lajos Kemeny senior, and Steven Gygi for helpful discussions. E.R. gratefully acknowledges support from the Mildred Scheel Grant of the German Cancer Society and the Filling the Gap Grant of the University of Zurich , Switzerland. D.E.F. gratefully acknowledges support from NIH grants 5P01-CA163222 , 5R01CA222871 , 5R01AR043369 , and 5R01AR072304 and the Dr. Miriam and Sheldon Adelson Medical Research Foundation . S.T. is funded by NIH grants R01AR076241 and R35 GM134957-01 . This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center ( National Center for Advancing Translational Sciences , National Institutes of Health award UL 1TR002541 ) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. P.P.N. was supported by the Swiss National Science Foundation (SNSF). Early Postdoctoral Mobility Fellowship CRSII3_154461 and Postdoctoral Mobility Fellowship P400PB_199252 . B.P.K. was supported by NCI R00 CA218870 and NHLBI P01 HL142494 . K.A. was supported by the Santander Research and Scholarship Award, and Bogue Fellowship from University College London . A.R.L. was supported by the Leverhulme Trust ( F/07 134/DF ), BBSRC ( BB/I021213/1 ), the Excellence Initiative of Aix-Marseille University - A ∗ MIDEX (a French “Investissements d’Avenir” program, 2RUIZLRE/RHRE/ID18HRU201 and 20-07874 ), the National Natural Science Foundation of China ( 31771393 ), the Scientific and Technology Committee of Shanghai Municipality ( 18490750300 ), the Ministry of Science and Technology of China ( 2020YFE0201600 ), the Shanghai Municipal Science and Technology Major Project ( 2017SHZDZX01 ), and the 111 Project ( B13016 ). G.B. was supported by the Universidad de Antioquia ( CODI sostenibilidad de grupos 2013–2014 and MASO 2013–2014 ). L.V.K. is a recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam (the Netherlands); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly ; the Ministry of Education, Culture and Science ; the Ministry for Health, Welfare and Sports ; the European Commission (DG XII); and the Municipality of Rotterdam . The Microscopy Core of the MGH Program in Membrane Biology is partially supported by Inflammatory Bowel Disease Center grant DK043351 and Boston Area Diabetes Endocrinology Research Center grant DK057521 . Funding Information: We thank C. Thomas Powell and Robert Liu for help with statistical analysis and editing, Diane Capen for help with electron microscopy-related questions, Sharon Germana for administrative help, Paolo Gameiro for providing plasmid constructs, Pawel Pelczar for his efforts to generate transgenic mice, and Ruth Halaban, Micky Marks, Doug Richardson, Desmond Tobin, Rizwan Haq, Pere Puigserver, Alfred Goldberg, Lajos Kemeny senior, and Steven Gygi for helpful discussions. E.R. gratefully acknowledges support from the Mildred Scheel Grant of the German Cancer Society and the Filling the Gap Grant of the University of Zurich, Switzerland. D.E.F. gratefully acknowledges support from NIH grants 5P01-CA163222, 5R01CA222871, 5R01AR043369, and 5R01AR072304 and the Dr. Miriam and Sheldon Adelson Medical Research Foundation. S.T. is funded by NIH grants R01AR076241 and R35 GM134957-01. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. P.P.N. was supported by the Swiss National Science Foundation (SNSF). Early Postdoctoral Mobility Fellowship CRSII3_154461 and Postdoctoral Mobility Fellowship P400PB_199252. B.P.K. was supported by NCI R00 CA218870 and NHLBI P01 HL142494. K.A. was supported by the Santander Research and Scholarship Award, and Bogue Fellowship from University College London. A.R.L. was supported by the Leverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative of Aix-Marseille University - A∗MIDEX (a French “Investissements d'Avenir” program, 2RUIZLRE/RHRE/ID18HRU201 and 20-07874), the National Natural Science Foundation of China (31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), the Ministry of Science and Technology of China (2020YFE0201600), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the 111 Project (B13016). G.B. was supported by the Universidad de Antioquia (CODI sostenibilidad de grupos 2013–2014 and MASO 2013–2014). L.V.K. is a recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam (the Netherlands); the Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The Microscopy Core of the MGH Program in Membrane Biology is partially supported by Inflammatory Bowel Disease Center grant DK043351 and Boston Area Diabetes Endocrinology Research Center grant DK057521. E.R. and D.E.F. conceived the project. E.R. J.A. I.R. and D.E.F. designed and discussed the experiments. E.R. I.R. J.A. Y.S. S.K. A.K. V.I. J.Z. H.W. A.L. M.V.S. K.W. B.P.K. K.A.C. and S.I. performed in vitro studies. J.A. I.R. and J.H.L. performed histological analyses. A.C. H.R.N. and L.Z. performed zebrafish experiments. E.R. V.I. J.A. and J.A.L. performed mouse studies and prepared photographic images. K.A. L.M.P. S.F. R.G.-J. M.-C.B. S.C.-Q. V.A.-A. C.G. G.P. G.B. F.R. T.N. S.T. and A.R.-L. performed human genetic association studies. C.M.L. N.M. J.A.L. C.H.W. S.O. J.Z. N.N. Q.Y.W. H.W. C.L.E. M.V.S. P.P.N. K.I. I.N. L.H.C. A.A.N. J.J.H. C.B. and T.R. assisted with the experimental design and data interpretation. E.R. J.A. I.R,. K.A. L.M.P. and S.K. prepared figures. E.R. I.R. K.A. J.A. and D.E.F. wrote the manuscript. All authors discussed the results and commented on the manuscript. D.E.F. and E.R. have a patent filed on “Methods and compositions for enhancing skin pigmentation” (publication number WO/2016/077817, May 19, 2016.). D.E.F. has a financial interest in Soltego, Inc. a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. D.E.F.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. B.P.K. is an inventor on patents and patent applications filed by Mass General Brigham that describe genome engineering technologies. B.P.K. consults for Avectas Inc. ElevateBio, and EcoR1 capital and is an advisor to Acrigen Biosciences. Q.Y.W. is a shareholder in Mymiel Skincare. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, and Scholar Rock. He is a consultant for Celularity and Cellarity. H.W. is an employee and shareholder of Johnson and Johnson. Publisher Copyright: © 2021 Elsevier Inc.

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.

UR - http://www.scopus.com/inward/record.url?scp=85111783140&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85111783140&partnerID=8YFLogxK

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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