{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T03:10:54Z","timestamp":1782357054540,"version":"3.54.5"},"posted":{"date-parts":[[2023,5,26]]},"group-title":"Cell Biology","reference-count":62,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signaling. However, role of mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  uptake.\n                  <jats:italic>In vitro<\/jats:italic>\n                  gain and loss of function studies demonstrated that Mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  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\n                  <jats:italic>in vivo<\/jats:italic>\n                  . 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\n                  <jats:sup>2+<\/jats:sup>\n                  uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:p>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>\n                          MCU complex mediated mitochondrial Ca\n                          <jats:sup>2+<\/jats:sup>\n                          uptake is a novel regulator of vertebrate pigmentation\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          Keratin filaments bridge mitochondrial Ca\n                          <jats:sup>2+<\/jats:sup>\n                          signaling to melanosome biogenesis and maturation\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          Transcription factor NFAT2 connects mitochondrial Ca\n                          <jats:sup>2+<\/jats:sup>\n                          dynamics to keratins expression\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          MCU-NFAT2-Keratin 5 signaling module generates a negative feedback loop to maintain mitochondrial Ca\n                          <jats:sup>2+<\/jats:sup>\n                          homeostasis and to ensure optimal melanogenesis\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Inhibiting MCU with mitoxantrone, an FDA approved drug, leads to reduction in physiological pigmentation<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.05.26.542250","type":"posted-content","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T21:15:22Z","timestamp":1685135722000},"source":"Crossref","is-referenced-by-count":2,"title":["Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis"],"prefix":"10.64898","author":[{"given":"Jyoti","family":"Tanwar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kriti","family":"Ahuja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paras","family":"Sehgal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyan","family":"Ranjan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farina","family":"Sultan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshu","family":"Priya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manigandan","family":"Venkatesan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vamsi 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