Mitochondrial calcium uptake orchestrates vertebrate pigmentation via transcriptional regulation of keratin filaments

• DOI: 10.1371/journal.pbio.3002895
• Publication Date: 2024-11-11T18:46:49Z
• Authors: Jyoti Tanwar; Kriti Ahuja; Akshay Sharma; Paras Sehgal; Gyan Ranjan; Farina Sultan; Anushka Agrawal; Donato D’Angelo; Anshu Priya; Vamsi K. Yenamandra; Archana Singh; Anna Raffaello; Muniswamy Madesh; Rosario Rizzuto; Sridhar Sivasubbu; Rajender K. Motiani
• Keywords: QH301-705.5; Biology (General); Research Article

Mitochondria regulate several physiological functions through mitochondrial Ca 2+ dynamics. However, role of signaling in melanosome biology remains unknown. Here, we show that pigmentation requires uptake. In vitro gain and loss function studies demonstrate uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, +/- -/- mice models complex drives vivo. Mechanistically, silencing activates transcription factor NFAT2 to induce expression keratin (5, 7, 8) filaments. Interestingly, keratin5 turn augments uptake potentiates by regulating biogenesis maturation. Hence this module acts as a negative feedback loop fine-tunes both pigmentation. Notably, mitoxantrone, an FDA approved drug inhibits MCU, reduces thereby highlighting therapeutic potential targeting clinical management pigmentary disorders. Taken together, reveal MCU-NFAT2-Keratin5 driven axis critical determinant Given the vital filaments cellular physiology, could be operational variety other patho-physiological processes.