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

Abstract

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.

Lipid droplets are a metabolic vulnerability in melanoma

“…Across melanoma cell lines and primary patient melanomas, we found that acquisition of melanocytic identity corresponds with enhanced fatty acid uptake and oxidation. Interestingly, a recent study found that the process of melanogenesis relies on elevated fatty acid oxidation in melanocytes and mouse B16 melanoma cells 56 . Our data support the idea that melanocytic identity and dependence on lipid metabolism are intrinsically coupled.…”

MITF is a novel transcriptional regulator of the calcium sensor STIM1: Significance in physiological melanogenesis

“…We have established a B16 (mouse melanoma cell line)-based LD culturing–induced pigmentation model ( 9 ). This model closely recapitulates the melanogenic pathways and signaling cascades operating in primary human melanocytes ( 9 , 24 , 25 ). The LD-pigmentation model leads to a gradual increase in pigmentation over a 7-day period wherein the day-zero (D0) cells are depigmented; by day four (D4), the pigmentation machinery becomes activated and cells become completely pigmented by day seven (D7) ( Fig.…”

Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis

“…During LD pigmentation, non-pigmented B16 cells are seeded at a density of 100 cells/cm 2 and over a period of 6-8 days these cells become highly pigmented (Motiani, Tanwar et al, 2018;Natarajan, Ganju et al, 2014b) (Figure 1A). The LD pigmentation model closely recapitulates human melanogenic pathways (Motiani et al, 2018;Natarajan et al, 2014b;Sultan, Basu et al, 2022;Tanwar, Sharma et al, 2022b). We quantitated the increase in the melanogenesis during LD pigmentation model by performing melanin content assay, which showed a gradual increase in melanin synthesis from LD day 0 (D0) to LD day 4 (D4), LD day 5 (D5) and LD day 6 (D6) (Figure 1B).…”