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

Abstract

AbstractMitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca2+signaling. However, role of mitochondrial Ca2+signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+uptake.In vitrogain and loss of function studies demonstrated that Mitochondrial Ca2+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 pigmentationin 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 Ca2+uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca2+signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca2+signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.HighlightsMCU complex mediated mitochondrial Ca2+uptake is a novel regulator of vertebrate pigmentationKeratin filaments bridge mitochondrial Ca2+signaling to melanosome biogenesis and maturationTranscription factor NFAT2 connects mitochondrial Ca2+dynamics to keratins expressionMCU-NFAT2-Keratin 5 signaling module generates a negative feedback loop to maintain mitochondrial Ca2+homeostasis and to ensure optimal melanogenesisInhibiting MCU with mitoxantrone, an FDA approved drug, leads to reduction in physiological pigmentation