Temporal analysis of melanogenesis identifies fatty acid metabolism as key skin pigment regulator

• Published in: PLoS biology Vol. 20; no. 5; p. e3001634
• Main Authors: Sultan, Farina, Basu, Reelina, Murthy, Divya, Kochar, Manisha, Attri, Kuldeep S, Aggarwal, Ayush, Kumari, Pooja, Dnyane, Pooja, Tanwar, Jyoti, Motiani, Rajender K, Singh, Archana, Gadgil, Chetan, Bhavesh, Neel Sarovar, Singh, Pankaj K, Natarajan, Vivek T, Gokhale, Rajesh S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18-05-2022; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Biology and Life Sciences; Channeling; Channelization; Circuits; Fatty acid metabolism; Fatty Acids; Genes; Genetic engineering; Glucose; Glycolysis; Guinea Pigs; Lipid Metabolism; Lipids; Medicine and Health Sciences; Melanins - metabolism; Melanocytes; Metabolism; Metabolites; Mitochondria; Oxidation; Phenotypes; Physical Sciences; Pigmentation; Research and Analysis Methods; Skin; Skin cancer; Skin Pigmentation; Software; Synthesis; Tanning; Therapeutic targets; United States; India; Turkey
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001634

Therapeutic methods to modulate skin pigmentation has important implications for skin cancer prevention and for treating cutaneous hyperpigmentary conditions. Towards defining new potential targets, we followed temporal dynamics of melanogenesis using a cell-autonomous pigmentation model. Our study elucidates 3 dominant phases of synchronized metabolic and transcriptional reprogramming. The melanogenic trigger is associated with high MITF levels along with rapid uptake of glucose. The transition to pigmented state is accompanied by increased glucose channelisation to anabolic pathways that support melanosome biogenesis. SREBF1-mediated up-regulation of fatty acid synthesis results in a transient accumulation of lipid droplets and enhancement of fatty acids oxidation through mitochondrial respiration. While this heightened bioenergetic activity is important to sustain melanogenesis, it impairs mitochondria lately, shifting the metabolism towards glycolysis. This recovery phase is accompanied by activation of the NRF2 detoxication pathway. Finally, we show that inhibitors of lipid metabolism can resolve hyperpigmentary conditions in a guinea pig UV-tanning model. Our study reveals rewiring of the metabolic circuit during melanogenesis, and fatty acid metabolism as a potential therapeutic target in a variety of cutaneous diseases manifesting hyperpigmentary phenotype.