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- W4366184021 abstract "Human pigmentation can be a risk factor for multiple diseases of the skin and eyes. Pigmentation in the skin and eyes is the consequence of differing amounts of eumelanin and pheomelanin, which have anti-oxidant and pro-oxidant properties, respectively. Substantial work has established the importance of melanin synthesis for blocking DNA damage from ultraviolet radiation (UV); however, there are diseases associated with pigmentation (e.g., acral lentignous, mucosal, and uveal melanoma) that are independent of UV radiation suggesting that melanin may directly impact cellular biology. Recent work has suggested that mitochondria and melanosomes, the melanin synthesizing organelle, form physical contacts with each other, suggesting that melanosome biology may impact mitochondrial metabolism. Therefore, we asked whether melanin metabolism directly affects global cellular metabolism and is a potential mechanism for pigmentation-dependent disease risk in the skin and eyes. We developed a panel of syngeneic melanocytes that have wild type pigmentation or harbor a CRISPR-induced genetic knockout of tyrosinase, DCT, SLC45A2, OCA2, or TPC2. Using a recently established tyrosine tracing LC-MS method, we have discovered that melanin synthesis affects multiple metabolic pathways in melanocytes including glycolysis, amino acid metabolism, and mitochondrial metabolism. Furthermore, we find that melanin synthesis increases mitochondrial number and mass with concomitant loss of mitochondrial polarization and electron transport chain activity. Melanin synthesis and mitochondrial respiration have significant effects on reactive oxygen species (ROS) and we find that both intracellular and extracellular ROS levels are driven by melanin metabolism in the absence of UV radiation. Finally, using MS imaging techniques, we find that pigment cells with different levels of melanin synthesis affect cellular metabolism in adjacent cells. In conclusion, we have identified melanin synthesis as a important regulator of cellular and tissue metabolism independent of UV." @default.
- W4366184021 created "2023-04-19" @default.
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- W4366184021 date "2023-05-01" @default.
- W4366184021 modified "2023-10-01" @default.
- W4366184021 title "1280 Melanin synthesis drives global reprogramming of cellular and tissue metabolism" @default.
- W4366184021 doi "https://doi.org/10.1016/j.jid.2023.03.1294" @default.
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