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Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation

Inter-organellar communication is emerging as one of the most crucial regulators of cellular physiology. One of the key regulators of inter-organellar communication is Mitofusin-2 (MFN2). MFN2 is also involved in mediating mitochondrial fusion–fission dynamics. Further, it facilitates mitochondrial...

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Autores principales: Tanwar, Jyoti, Saurav, Suman, Basu, Reelina, Singh, Jaya Bharti, Priya, Anshu, Dutta, Maitreyee, Santhanam, Uma, Joshi, Manoj, Madison, Stephen, Singh, Archana, Nair, Nirmala, Gokhale, Rajesh S., Motiani, Rajender K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869806/
https://www.ncbi.nlm.nih.gov/pubmed/35203350
http://dx.doi.org/10.3390/cells11040701
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author Tanwar, Jyoti
Saurav, Suman
Basu, Reelina
Singh, Jaya Bharti
Priya, Anshu
Dutta, Maitreyee
Santhanam, Uma
Joshi, Manoj
Madison, Stephen
Singh, Archana
Nair, Nirmala
Gokhale, Rajesh S.
Motiani, Rajender K.
author_facet Tanwar, Jyoti
Saurav, Suman
Basu, Reelina
Singh, Jaya Bharti
Priya, Anshu
Dutta, Maitreyee
Santhanam, Uma
Joshi, Manoj
Madison, Stephen
Singh, Archana
Nair, Nirmala
Gokhale, Rajesh S.
Motiani, Rajender K.
author_sort Tanwar, Jyoti
collection PubMed
description Inter-organellar communication is emerging as one of the most crucial regulators of cellular physiology. One of the key regulators of inter-organellar communication is Mitofusin-2 (MFN2). MFN2 is also involved in mediating mitochondrial fusion–fission dynamics. Further, it facilitates mitochondrial crosstalk with the endoplasmic reticulum, lysosomes and melanosomes, which are lysosome-related organelles specialized in melanin synthesis within melanocytes. However, the role of MFN2 in regulating melanocyte-specific cellular function, i.e., melanogenesis, remains poorly understood. Here, using a B16 mouse melanoma cell line and primary human melanocytes, we report that MFN2 negatively regulates melanogenesis. Both the transient and stable knockdown of MFN2 leads to enhanced melanogenesis, which is associated with an increase in the number of mature (stage III and IV) melanosomes and the augmented expression of key melanogenic enzymes. Further, the ectopic expression of MFN2 in MFN2-silenced cells leads to the complete rescue of the phenotype at the cellular and molecular levels. Mechanistically, MFN2-silencing elevates mitochondrial reactive-oxygen-species (ROS) levels which in turn increases melanogenesis. ROS quenching with the antioxidant N-acetyl cysteine (NAC) reverses the MFN2-knockdown-mediated increase in melanogenesis. Moreover, MFN2 expression is significantly lower in the darkly pigmented primary human melanocytes in comparison to lightly pigmented melanocytes, highlighting a potential contribution of lower MFN2 levels to higher physiological pigmentation. Taken together, our work establishes MFN2 as a novel negative regulator of melanogenesis.
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spelling pubmed-88698062022-02-25 Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation Tanwar, Jyoti Saurav, Suman Basu, Reelina Singh, Jaya Bharti Priya, Anshu Dutta, Maitreyee Santhanam, Uma Joshi, Manoj Madison, Stephen Singh, Archana Nair, Nirmala Gokhale, Rajesh S. Motiani, Rajender K. Cells Article Inter-organellar communication is emerging as one of the most crucial regulators of cellular physiology. One of the key regulators of inter-organellar communication is Mitofusin-2 (MFN2). MFN2 is also involved in mediating mitochondrial fusion–fission dynamics. Further, it facilitates mitochondrial crosstalk with the endoplasmic reticulum, lysosomes and melanosomes, which are lysosome-related organelles specialized in melanin synthesis within melanocytes. However, the role of MFN2 in regulating melanocyte-specific cellular function, i.e., melanogenesis, remains poorly understood. Here, using a B16 mouse melanoma cell line and primary human melanocytes, we report that MFN2 negatively regulates melanogenesis. Both the transient and stable knockdown of MFN2 leads to enhanced melanogenesis, which is associated with an increase in the number of mature (stage III and IV) melanosomes and the augmented expression of key melanogenic enzymes. Further, the ectopic expression of MFN2 in MFN2-silenced cells leads to the complete rescue of the phenotype at the cellular and molecular levels. Mechanistically, MFN2-silencing elevates mitochondrial reactive-oxygen-species (ROS) levels which in turn increases melanogenesis. ROS quenching with the antioxidant N-acetyl cysteine (NAC) reverses the MFN2-knockdown-mediated increase in melanogenesis. Moreover, MFN2 expression is significantly lower in the darkly pigmented primary human melanocytes in comparison to lightly pigmented melanocytes, highlighting a potential contribution of lower MFN2 levels to higher physiological pigmentation. Taken together, our work establishes MFN2 as a novel negative regulator of melanogenesis. MDPI 2022-02-16 /pmc/articles/PMC8869806/ /pubmed/35203350 http://dx.doi.org/10.3390/cells11040701 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tanwar, Jyoti
Saurav, Suman
Basu, Reelina
Singh, Jaya Bharti
Priya, Anshu
Dutta, Maitreyee
Santhanam, Uma
Joshi, Manoj
Madison, Stephen
Singh, Archana
Nair, Nirmala
Gokhale, Rajesh S.
Motiani, Rajender K.
Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation
title Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation
title_full Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation
title_fullStr Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation
title_full_unstemmed Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation
title_short Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation
title_sort mitofusin-2 negatively regulates melanogenesis by modulating mitochondrial ros generation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869806/
https://www.ncbi.nlm.nih.gov/pubmed/35203350
http://dx.doi.org/10.3390/cells11040701
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