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Stress chaperone mortalin regulates human melanogenesis

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Cell Stress and Chaperones Aims and scope

Abstract

In order to identify the cellular factors involved in human melanogenesis, we carried out shRNA-mediated loss-of-function screening in conjunction with induction of melanogenesis by 1-oleoyl-2-acetyl-glycerol (OAG) in human melanoma cells using biochemical and visual assays. Gene targets of the shRNAs (that caused loss of OAG-induced melanogenesis) and their pathways, as determined by bioinformatics, revealed involvement of proteins that regulate cell stress response, mitochondrial functions, proliferation, and apoptosis. We demonstrate, for the first time, that the mitochondrial stress chaperone mortalin is crucial for melanogenesis. Upregulation of mortalin was closely associated with melanogenesis in in vitro cell-based assays and clinical samples of keloids with hyperpigmentation. Furthermore, its knockdown resulted in compromised melanogenesis. The data proposed mortalin as an important protein that may be targeted to manipulate pigmentation for cosmetic and related disease therapeutics.

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Acknowledgments

We thank T. Nakamoto, R. Singh, T. Yaguchi, and N. Shah for their help.

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Author notes

  1. Didik Priyandoko

    Present address: Department of Biology, Universitas Pendidikan Indonesia, Bandung, Indonesia

  2. Nashi Widodo

    Present address: Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, Indonesia

Authors and Affiliations

  1. DAILAB, National Institute of Advanced Industrial Science and Technology (AIST), Central 5-41, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8565, Japan

    Renu Wadhwa, Didik Priyandoko, Ran Gao, Nashi Widodo, Nupur Nigam, Ling Li & Sunil C. Kaul

  2. Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-Ro, Seongdong-Gu, Seoul, 133-791, South Korea

    Hyo Min Ahn & Chae-Ok Yun

  3. KK Chanel Research and Technology Development Laboratory, 1-1-5, Yamate, Funabashi-Chiba, 273-0045, Japan

    Nobuhiro Ando & Christian Mahe

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Author Contributions

RW and SCK conceived and coordinated the study and wrote the paper. RW, DP, RG, NW, NN, LL, and HA performed the experiments. RW, COY, NA, CM, and SCK analyzed the data. All authors reviewed the results and approved the final version of the manuscript.

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Supplementary Fig. 1

Schematic diagram showing loss-of-function screening for genes involved in melanogenesis pathway. Cells were transfected with shRNAs. Transfected cells were selected in puromycin-supplemented medium and then subjected to OAG treatment. Melanin content, tyrosinase activity, and melanosome staining were performed in parallel. The shRNAs that caused reduction in all the three parameters were selected for the next round. In total, four rounds of screening were done. (GIF 14 kb)

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Supplementary Fig. 2

Effect of mitochondrial inhibitors and OAG on ROS and mitochondrial membrane potential. H2O2 was used as a positive control for oxidative stress. It caused increase in ROS and collapse of mitochondrial membrane potential (loss of red staining). Creatine and OAG caused similar, although somewhat milder effect as revealed by increase in ROS staining and loss of red staining. (GIF 15 kb)

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Wadhwa, R., Priyandoko, D., Gao, R. et al. Stress chaperone mortalin regulates human melanogenesis. Cell Stress and Chaperones 21, 631–644 (2016). https://doi.org/10.1007/s12192-016-0688-2

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