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

Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca(2+) signaling. However, role of mitochondrial Ca(2+) signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca(2+) uptake. In vitro gain and loss of function studies demonstrated that Mitochondrial Ca(2+) Uniporter (MCU) is crucial for melanogenesis while the MCU rheostats, MCUb and MICU1 negatively control melanogenesis. Zebrafish and mouse models showed that MCU plays a vital role in pigmentation in vivo. Mechanistically, MCU controls activation of transcription factor NFAT2 to induce expression of three keratins (keratin 5, 7 and 8), which we report as positive regulators of melanogenesis. Interestingly, keratin 5 in turn modulates mitochondrial Ca(2+) uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca(2+) signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca(2+) signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca(2+) signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.