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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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/4/701 |
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| author | Jyoti Tanwar Suman Saurav Reelina Basu Jaya Bharti Singh Anshu Priya Maitreyee Dutta Uma Santhanam Manoj Joshi Stephen Madison Archana Singh Nirmala Nair Rajesh S. Gokhale Rajender K. Motiani |
| author_facet | Jyoti Tanwar Suman Saurav Reelina Basu Jaya Bharti Singh Anshu Priya Maitreyee Dutta Uma Santhanam Manoj Joshi Stephen Madison Archana Singh Nirmala Nair Rajesh S. Gokhale Rajender K. Motiani |
| author_sort | Jyoti Tanwar |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T22:19:59Z |
| format | Article |
| id | doaj.art-3cd3972278a54e9a8b69b98abe01bd8b |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T22:19:59Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3cd3972278a54e9a8b69b98abe01bd8b2023-11-23T19:15:38ZengMDPI AGCells2073-44092022-02-0111470110.3390/cells11040701Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS GenerationJyoti Tanwar0Suman Saurav1Reelina Basu2Jaya Bharti Singh3Anshu Priya4Maitreyee Dutta5Uma Santhanam6Manoj Joshi7Stephen Madison8Archana Singh9Nirmala Nair10Rajesh S. Gokhale11Rajender K. Motiani12CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 110025, IndiaLaboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad 121001, Delhi-NCR, IndiaCSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 110025, IndiaLaboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad 121001, Delhi-NCR, IndiaCSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 110025, IndiaUnilever R and D, Bangalore 560066, IndiaUnilever R and D, Bangalore 560066, IndiaUnilever R and D, Bangalore 560066, IndiaUnilever R and D, Bangalore 560066, IndiaCSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 110025, IndiaUnilever R and D, Bangalore 560066, IndiaCSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 110025, IndiaLaboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad 121001, Delhi-NCR, IndiaInter-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.https://www.mdpi.com/2073-4409/11/4/701MFN2reactive oxygen speciesmelanogenesismelanosomemitochondria |
| spellingShingle | Jyoti Tanwar Suman Saurav Reelina Basu Jaya Bharti Singh Anshu Priya Maitreyee Dutta Uma Santhanam Manoj Joshi Stephen Madison Archana Singh Nirmala Nair Rajesh S. Gokhale Rajender K. Motiani Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation Cells MFN2 reactive oxygen species melanogenesis melanosome mitochondria |
| 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 | MFN2 reactive oxygen species melanogenesis melanosome mitochondria |
| url | https://www.mdpi.com/2073-4409/11/4/701 |
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