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

by 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

Mitochondria regulate several physiological functions through mitochondrial Ca²⁺ dynamics. However, role of mitochondrial Ca²⁺ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca²⁺ uptake. In vitro gain and loss of function studies demonstrate that mitochondrial Ca²⁺ uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, MCU^+/- and MCUb^-/- mice models show that MCU complex drives pigmentation in vivo. Mechanistically, MCU silencing activates transcription factor NFAT2 to induce expression of keratin (5, 7, and 8) filaments. Interestingly, keratin5 in turn augments mitochondrial Ca²⁺ uptake and potentiates melanogenesis by regulating melanosome biogenesis and maturation. Hence this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca²⁺ signaling and pigmentation. Notably, mitoxantrone, an FDA approved drug that inhibits MCU, reduces pigmentation thereby highlighting therapeutic potential of targeting mitochondrial Ca²⁺ uptake for clinical management of pigmentary disorders. Taken together, we reveal an MCU-NFAT2-Keratin5 driven signaling axis that acts as a critical determinant of mitochondrial Ca²⁺ uptake and pigmentation. Given the vital role of mitochondrial Ca²⁺ signaling and keratin filaments in cellular physiology, this feedback loop could be operational in a variety of other patho-physiological processes.